Composition comprising a benzoate salt of 5-methoxy-n,n-dimethyltryptamine

ABSTRACT

A composition comprising a pharmaceutically effective amount of a pharmaceutically acceptable benzoate salt of 5-methoxy-N,N-dimethyltryptamine (5MeODMT).

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. Application No. 17/817,548,filed on Aug. 4, 2022, which is a continuation of U.S. Application No.17/660,873, filed on Apr. 27, 2022, now U.S. Pat. No. 11,518,742, whichis a continuation of International Application No. PCT/GB2021/051475,filed on Jun. 14, 2021, each of which is incorporated by referenceherein, PCT/GB2021/051475 claiming the benefit of priority to GBApplication No. 2008964.5, filed on Jun. 12, 2020, GB Application No.2008961.1, filed on Jun. 12, 2020, GB Application No. 2008968.6, filedon Jun. 12, 2020, GB Application No. 2019241.5, filed on Dec. 7, 2020,GB Application No. 2101640.7, filed on Feb. 5, 2021, GB Application No.2101634.0, filed on Feb. 5, 2021, GB Application No. 2102100.1, filed onFeb. 15, 2021, GB Application No. 2102095.3, filed on Feb. 15, 2021, GBApplication No. 2105049.7, filed on Apr. 8, 2021, GB Application No.2105047.1, filed on Apr. 8, 2021, and GB Application No. 2105462.2,filed on Apr. 16, 2021.

FIELD OF THE INVENTION

This invention relates to pharmaceutically acceptable salts of5-methoxy-N,N-dimethyltryptamine. In particular, though not exclusively,the invention relates to formulations and uses of the same as amedicament.

BACKGROUND OF THE INVENTION

5-methoxy-N,N-dimethyltryptamine (5MeODMT) is a pharmacologically activecompound of the tryptamine class and has the chemical formula:

5MeODMT is a psychoactive/psychedelic substance found in nature and isbelieved to act mainly through serotonin receptors. It is also believedto have a high affinity for the 5-HT₂ and 5-HT_(1A) subtypes, and/orinhibits monoamine reuptake.

However, 5MeODMT is not well understood and uses of this compound havenot been well explored. Further, 5MeODMT is not easy to handle, andthere are challenges in formulating it for effective delivery inpharmaceutically useful compositions.

There remains a need in the art for improved formulations and uses of5MeODMT.

SUMMARY OF THE INVENTION

Herein disclosed, there is provided a composition comprising apharmaceutically effective amount of a pharmaceutically acceptable saltof 5-methoxy-N,N-dimethyltryptamine (5MeODMT).

In an embodiment, the salt anion is an aryl carboxylate. In anembodiment, the aryl carboxylate is substituted with one to three Rgroups.

In an embodiment the one or more R groups are independently selectedfrom: alkynyl, carbonyl, aldehyde, haloformyl, alkyl, halide, hydroxy,alkoxy, carbonate ester, carboxylate, carboxyl, carboalkoxy, methoxy,hydroperoxy, peroxy, ether, hemiacetal, hemiketal, acetal, ketal,orthoester, methylenedioxy, orthocarbonate ester, carboxylic anhydride,carboxamide, secondary, tertiary or quaternary amine, primary orsecondary ketimine, primary or secondary aldimine, imide, azide, azo,cyanate, isocyanate, nitrate, nitrile, isonitrile, nitrosooxy, nitro,nitroso, oxime, pyridyl, carbamate, sulfhydryl, sulfide, disulfide,sulfinyl, sulfonyl, sulfino, sulfo, thiocyanate, isothiocyanate,carbonothioyl, carbothioic S-acid, carbothioic O-acid, thiolester,thionoester, carbodithioic acid, carbodithio, phosphino, phosphono,phosphate, borono, boronate, borino or borinate.

In an embodiment the one or more R groups are independently selectedfrom: C₁ - C₆ alkyl, C₁ - C₆ alkoxy, C₁ - C₆ alkenyl or C₁ - C₆ alkynyl,and where each of these may be optionally substituted with one to threeR groups as previously described.

In a first aspect of the invention, there is provided a compositioncomprising a pharmaceutically effective amount of a pharmaceuticallyacceptable benzoate salt of 5-methoxy-N,N-dimethyltryptamine (5MeODMT).

The invention provides for improved formulations and uses of 5MeODMTsalts.

In an embodiment the composition comprises a dosage amount of 5MeODMT inthe range of 0.05 mg to 100 mg.

In an embodiment the composition comprises a dosage amount of 5MeODMT inthe range of 0.1 mg to 50 mg.

In an embodiment the composition comprises a dosage amount of 5MeODMT inthe range of 0.5 mg to 25 mg.

In an embodiment the composition comprises a dosage amount of 5MeODMT inthe range of 0.5 mg to 10 mg.

In an embodiment the composition comprises a dosage amount of 5MeODMT inthe range of 1 mg to 10 mg.

In an embodiment the composition comprises a dosage amount of 5MeODMT inthe range of 1 mg to 8 mg.

In an embodiment the composition comprises a dosage amount of 5MeODMT inthe range of 3 mg to 15 mg.

In an embodiment the composition comprises a dosage amount of 5MeODMT inthe range of 0.005 mg to 100 mg.

In an embodiment the composition comprises a dosage amount of 5MeODMT inthe range of 0.001 mg to 100 mg.

In an embodiment the composition comprises a dosage amount of 5MeODMT inthe range of 0.0005 mg to 100 mg.

The level of the active agent can be adjusted as required by need forexample to suit a certain patient group (e.g. the elderly) or theconditions being treated.

In an embodiment the composition is formulated in a dosage form selectedfrom: oral, transdermal, inhalable, intravenous, or rectal dosage form.

It is advantageous to be able to deliver the active agent in differentforms, for example to suit a certain patient group (e.g. the elderly) orthe conditions being treated.

In an embodiment the composition is formulated in a dosage form selectedfrom: tablet, capsule, granules, powder, free-flowing powder, inhalablepowder, aerosol, nebulised, vaping, buccal, sublingual, sublabial,injectable, or suppository dosage form.

In an embodiment the powder is suitable for administration by inhalationvia a medicament dispenser selected from a reservoir dry powder inhaler,a unit-dose dry powder inhaler, a pre-metered multi-dose dry powderinhaler, a nasal inhaler or a pressurized metered dose inhaler.

In an embodiment the powder comprises particles, the particles having amedian diameter of less than 2000 µm, 1000 µm, 500 µm, 250 µm, 100 µm,50 µm, or 1 µm.

In an embodiment the powder comprises particles, the particles having amedian diameter of greater than 500 µm, 250 µm, 100 µm, 50 µm, 1 µm or0.5 µm.

In an embodiment the powder comprises particles, and wherein the powderhas a particle size distribution of d10=20-60 µm, and/or d50=80-120 µm,and/or d90=130-300 µm.

The nature of the powder can be adjusted to suit need. For example, ifbeing made for nasal inhalation, then the particles may be adjusted tobe much finer than if the powder is going to be formulated into agelatine capsule, or differently again if it is going to be compactedinto a tablet.

In an embodiment the 5MeODMT salt is amorphous or crystalline.

In an embodiment the 5MeODMT salt is in a polymorphic crystalline form,optionally 5MeODMT salt is Polymorph A.

In an embodiment the 5MeODMT salt is a benzoate, fumarate, citrate,acetate, succinate, halide, fluoride, chloride, bromide, iodide,oxalate, or triflate salt, optionally the salt is the chloride, benzoateor fumarate salt.

In an embodiment the 5MeODMT salt is formulated into a composition formucosal delivery. In an embodiment, the 5MeODMT salt is a benzoate salt.

In an embodiment, the 5MeODMT benzoate conforms to Pattern A ascharacterised by an XRPD diffractogram.

In an embodiment, the 5MeODMT benzoate is characterised by peaks in anXRPD diffractogram at 17.5, 17.7 and 21.0°2θ±0.1°2θ as measured by x-raypowder diffraction using an x-ray wavelength of 1.5406 Å.

In an embodiment, 5MeODMT benzoate is characterised by peaks in an XRPDdiffractogram as substantially illustrated in FIG. 6 or FIG. 7 .

In an embodiment, the 5MeODMT benzoate is characterised by bands at ca.3130, 1540, 1460, 1160 and 690 cm-1 in a fourier-transform infraredspectroscopy (FTIR) spectra.

In an embodiment, the 5MeODMT benzoate is characterised by a FTIRspectra for lot FP2 as substantially illustrated in FIG. 93 .

In an embodiment, the 5MeODMT benzoate conforms to Pattern B by XRPD.

In an embodiment, the 5MeODMT benzoate conforms to Pattern B ascharacterised by peaks in an XRPD diffractogram between 18.5 and 20°2Θ±0.1°2θ.

In an embodiment, the 5MeODMT benzoate conforms to Pattern B assubstantially illustrated by the XRPD diffractogram for lots P1, R1 andQ1 as substantially illustrated in FIG. 24 .

In an embodiment, the 5MeODMT benzoate conforms to Pattern B assubstantially illustrated by the XRPD diffractogram for lot R2 assubstantially illustrated in FIG. 28 .

In an embodiment, the 5MeODMT benzoate conforms to Pattern B assubstantially illustrated by the XRPD diffractogram for lots A1 and B1as substantially illustrated in FIGS. 38 or 39 .

In an embodiment, the 5MeODMT benzoate corresponds to the Pattern B formas characterised by FTIR spectra for lot C2 as substantially illustratedin FIG. 93 .

In an embodiment, the 5MeODMT benzoate corresponds to the Pattern C formas characterised by a minor broad endotherm with a peak temperature of108° C. in a DSC thermograph.

In an embodiment, the 5MeODMT benzoate corresponds to Pattern C ascharacterised by a DSC thermograph as substantially illustrated in FIG.65 .

In an embodiment, the 5MeODMT benzoate corresponds to the Pattern C formas characterised by a DSC thermograph as substantially illustrated inFIG. 66 .

In an embodiment, the 5MeODMT benzoate conforms to Pattern C by XRPD.

In an embodiment, the 5MeODMT benzoate conforms to Pattern C ascharacterised by a peak in an XRPD diffractogram at 10.3° 2Θ±0.1°2θ.

In an embodiment, the 5MeODMT benzoate conforms to Pattern C assubstantially illustrated by the XRPD diffractogram for lot A1 assubstantially illustrated in FIG. 68 .

In an embodiment, the 5MeODMT benzoate corresponds to the Pattern C formas characterised by FTIR spectra for lot C1 as substantially illustratedin FIG. 93 .

In an embodiment, the 5MeODMT benzoate conforms to Pattern D by XRPD.

In an embodiment, the 5MeODMT benzoate conforms to Pattern D assubstantially illustrated by the XRPD diffractogram in FIG. 73 or FIG.74 .

In an embodiment, the 5MeODMT benzoate corresponds to Pattern D ascharacterised by an endothermic event in a DSC thermograph at 118° C.

In an embodiment, the 5MeODMT benzoate corresponds to the Pattern D formas characterised by an endothermic event in a DSC thermograph at 118.58°C.

In an embodiment, the 5MeODMT benzoate conforms to Pattern E by XRPD.

In an embodiment, the 5MeODMT benzoate corresponds to Pattern E assubstantially illustrated by the XRPD diffractogram for lot D in FIG. 77or FIG. 78 .

In an embodiment, the 5MeODMT corresponds to the Pattern E form ascharacterised by a major bimodal endothermic event with peaktemperatures of 110.31° C. and 113.13° C. in a DSC thermograph.

In an embodiment, the 5MeODMT corresponds to Pattern E as characterisedby a minor endothermic event with a peak temperature of 119.09° C. in aDSC thermograph.

In an embodiment, the 5MeODMT corresponds to the Pattern E form ascharacterised by a DSC thermograph as substantially illustrated in FIG.79 .

In an embodiment, the 5MeODMT benzoate corresponds to Pattern E assubstantially illustrated by the XRPD diffractogram in FIG. 80 .

In an embodiment, the 5MeODMT benzoate corresponds to Pattern F by XRPD.

In an embodiment, the 5MeODMT benzoate conforms to Pattern F ascharacterised by an XRPD diffractogram for lot F (rerun) assubstantially illustrated in FIG. 84 .

In an embodiment, the 5MeODMT benzoate conforms to Pattern F ascharacterised by an XRPD diffractogram for lot F (rerun) assubstantially illustrated in FIG. 85 .

In an embodiment, the 5MeODMT benzoate conforms to Pattern F ascharacterised by an XRPD diffractogram for lot F (rerun) assubstantially illustrated in FIG. 89 .

In an embodiment, the 5MeODMT benzoate corresponds to the Pattern F formas characterised by endothermic events at 90° C., 106° C. and 180° C. ina DSC thermograph.

In an embodiment, the 5MeODMT benzoate corresponds to the Pattern F formas characterised by endothermic events at 90.50° C., 106.65° C. and180.35° C. in a DSC thermograph.

In an embodiment, the 5MeODMT benzoate conforms to Pattern G by XRPD.

In an embodiment, the 5MeODMT benzoate conforms to Pattern G, ascharacterised by an XRPD diffractogram for lot K as substantiallyillustrated in FIG. 87 .

In an embodiment, the 5MeODMT benzoate corresponds to the Pattern Gform, as characterised by an endothermic event in a DSC thermograph of119.61° C.

In an embodiment, the composition comprises 5MeODMT benzoate whichconforms to a mixture of two or more of Patterns A to G by XRPD.

For the salt, the dosage amount is the equivalent amount of the freebase delivered when the salt is taken. So 100 mg dosage amount of5MeODMT corresponds to 117 mg of the hydrochloride salt (i.e. bothproviding the same molar amount of the active substance). The greatermass of the salt needed is due to the larger formula weight of thehydrogen chloride salt (i.e. 218.3 g/mol for the free base as comparedto 254.8 g/mol for the salt). Similarly, for the deuterated ortriturated version of 5MeODMT (also considered within the scope of theinvention), a slight increase in mass can be expected due to theincreased formula weight of these isotopic compounds.

Amorphous and crystalline substances often show differentchemical/physical properties, e.g. improved rate of dissolution in asolvent, or improved thermal stability. Similarly, different polymorphsmay also show different and useful chemical/physical properties.

In an embodiment the composition comprises one or more pharmaceuticallyacceptable carriers or excipients.

In an embodiment the composition comprises one or more of: mucoadhesiveenhancer, penetrating enhancer, cationic polymers, cyclodextrins, TightJunction Modulators, enzyme inhibitors, surfactants, chelators, andpolysaccharides.

In an embodiment the composition comprises one or more of: chitosan,chitosan derivatives (such as N,N,N-trimethyl chitosan (TMC),n-propyl-(QuatPropyl), n-butyl-(QuatButyl) and n-hexyl(QuatHexyl)-N,N-dimethyl chitosan, chitosan chloride), β-cyclodextrin,clostridium perfringens enterotoxin, zonula occludens toxin (ZOT), humanneutrophil elastase inhibitor (ER143), sodium taurocholate, sodiumdeoxycholate sodium, sodium lauryl sulphate, glycodeoxycholat, palmiticacid, palmitoleic acid, stearic acid, oleyl acid, oleyl alchohol, capricacid sodium salt, DHA, EPA, dipalmitoyl phophatidyl choline, soybeanlecithin, lysophosphatidylcholine, dodecyl maltoside, tetradecylmaltoside, EDTA, lactose, cellulose, and citric acid.

In an embodiment the composition disclosed herein is for use as amedicament. In an embodiment the composition disclosed herein is for usein a method of treatment of a human or animal subject by therapy.

In an embodiment the method of treatment is a method of treatment of:

-   conditions caused by dysfunctions of the central nervous system,-   conditions caused by dysfunctions of the peripheral nervous system,-   conditions benefiting from sleep regulation (such as insomnia),-   conditions benefiting from analgesics (such as chronic pain),-   migraines,-   trigeminal autonomic cephalgias (such as short-lasting unilateral    neuralgiform headache with conjunctival injection and tearing    (SUNCT), and short-lasting neuralgiform headaches with cranial    autonomic symptoms (SUNA)),-   conditions benefiting from neurogenesis (such as stroke, traumatic    brain injury, Parkinson’s dementia),-   conditions benefiting from anti-inflammatory treatment,-   depression,-   treatment resistant depression-   anxiety,-   substance use disorder,-   addictive disorder,-   gambling disorder,-   eating disorders,-   obsessive-compulsive disorders, or-   body dysmorphic disorders,-   optionally the condition is SUNCT and/or SUNA.

Treatment of the above conditions may be beneficially improved by takingthe invention.

In an embodiment, the method of treatment is a method of treatment ofalcohol-related diseases and disorders, eating disorders, impulsecontrol disorders, nicotine-related disorders, tobacco-relateddisorders, methamphetamine-related disorders, amphetamine-relateddisorders, cannabis-related disorders, cocaine-related disorders,hallucinogen use disorders, inhalant-related disorders, benzodiazepineabuse or dependence related disorders, and/or opioid-related disorders.

In an embodiment, the method of treatment is a method of treatment oftobacco addiction. In an embodiment, the method is a method of reducingtobacco use. In an embodiment, the method of treatment is a method oftreatment of nicotine addiction. In an embodiment, the method is amethod of reducing nicotine use.

In an embodiment, the method of treatment is a method of treatingalcohol abuse and/or addiction. In an embodiment, the method oftreatment is a method of reducing alcohol use.

In an embodiment, the method of treatment is a method of treating orpreventing heavy drug use.

In an embodiment, the method of treatment is a method of treating orpreventing heavy drug use, including, but not limited to, alcohol,tobacco, nicotine, cocaine, methamphetamine, other stimulants,phencyclidine, other hallucinogens, marijuana, sedatives, tranquilizers,hypnotics, and opiates. It will be appreciated by one of ordinary skillin the art that heavy use or abuse of a substance does not necessarilymean the subject is dependent on the substance.

In an embodiment the method of treatment is a method of treatment ofmore than one of the above conditions, for example, the method oftreatment may be a method of treatment of depression and anxiety.

In an embodiment the composition is administered one or more times ayear.

In an embodiment the composition is administered one or more times amonth.

In an embodiment the composition is administered one or more times aweek.

In an embodiment the composition is administered one or more times aday.

In an embodiment the composition is administered at such a frequency asto avoid tachyphylaxis.

In an embodiment the composition is administered together with acomplementary treatment and/or with a further active agent.

In an embodiment the further active agent is a psychedelic compound,optionally a tryptamine.

In an embodiment the further active agent is lysergic acid diethylamide(LSD), psilocybin, psilocin or a prodrug thereof.

In an embodiment the further active agent is an antidepressant compound.

In an embodiment the further active agent is selected from an SSRI,SNRI, TCA or other antidepressant compounds.

In an embodiment the further active agent is selected from Citalopram(Celexa, Cipramil), Escitalopram (Lexapro, Cipralex), Fluoxetine(Prozac, Sarafem), Fluvoxamine (Luvox, Faverin), Paroxetine (Paxil,Seroxat), Sertraline (Zoloft, Lustral), Desvenlafaxine (Pristiq),Duloxetine (Cymbalta), Levomilnacipran (Fetzima), Milnacipran (Ixel,Savella), Venlafaxine (Effexor), Vilazodone (Viibryd), Vortioxetine(Trintellix), Nefazodone (Dutonin, Nefadar, Serzone), Trazodone(Desyrel), Reboxetine (Edronax), Teniloxazine (Lucelan, Metatone),Viloxazine (Vivalan), Bupropion (Wellbutrin), Amitriptyline (Elavil,Endep), Amitriptylinoxide (Amioxid, Ambivalon, Equilibrin), Clomipramine(Anafranil), Desipramine (Norpramin, Pertofrane), Dibenzepin (Noveril,Victoril), Dimetacrine (Istonil), Dosulepin (Prothiaden), Doxepin(Adapin, Sinequan), Imipramine (Tofranil), Lofepramine (Lomont,Gamanil), Melitracen (Dixeran, Melixeran, Trausabun), Nitroxazepine(Sintamil), Nortriptyline (Pamelor, Aventyl), Noxiptiline (Agedal,Elronon, Nogedal), Opipramol (Insidon), Pipofezine (Azafen/Azaphen),Protriptyline (Vivactil), Trimipramine (Surmontil), Amoxapine (Asendin),Maprotiline (Ludiomil), Mianserin (Tolvon), Mirtazapine (Remeron),Setiptiline (Tecipul), Isocarboxazid (Marplan), Phenelzine (Nardil),Tranylcypromine (Parnate), Selegiline (Eldepryl, Zelapar, Emsam),Caroxazone (Surodil, Timostenil), Metralindole (Inkazan), Moclobemide(Aurorix, Manerix), Pirlindole (Pirazidol), Toloxatone (Humoryl),Agomelatine (Valdoxan), Esketamine (Spravato), Ketamine (Ketalar),Tandospirone (Sediel), Tianeptine (Stablon, Coaxil), Amisulpride(Solian), Aripiprazole (Abilify), Brexpiprazole (Rexulti), Lurasidone(Latuda), Olanzapine (Zyprexa), Quetiapine (Seroquel), Risperidone(Risperdal), Trifluoperazine (Stelazine), Buspirone (Buspar), Lithium(Eskalith, Lithobid), Modafinil (Provigil), Thyroxine (T4),Triiodothyronine (T3).

In an embodiment the further active agent is selected from Celexa(citalopram), Cymbalta (duloxetine), Effexor (venlafaxine), Lexapro(escitalopram), Luvox (fluvoxamine), Paxil (paroxetine), Prozac(fluoxetine), Remeron (mirtazapine), Savella (milnacipran), Trintellix(vortioxetine), Vestra (reboxetine), Viibryd (vilazodone), Wellbutrin(bupropion), Zoloft (sertraline).

In an embodiment the complementary treatment is psychotherapy.

In an embodiment, there is provided a composition comprising apharmaceutically effective amount of a pharmaceutically acceptablebenzoate salt of 5MeODMT for use in a method of treatment of treatmentresistant depression.

In an embodiment, there is provided a composition comprising apharmaceutically effective amount of a pharmaceutically acceptablebenzoate salt of 5MeODMT for use in a method of treatment of depression.

In an embodiment, there is provided a composition comprising apharmaceutically effective amount of a pharmaceutically acceptablebenzoate salt of 5MeODMT for use in a method of treatment of PTSD.

In an embodiment, there is provided a composition comprising apharmaceutically effective amount of a pharmaceutically acceptablebenzoate salt of 5MeODMT for use in a method of treatment ofaddiction/substance misuse disorders.

In an embodiment, there is provided a nasal inhalation compositioncomprising a pharmaceutically effective amount of a pharmaceuticallyacceptable benzoate salt of 5MeODMT for use in a method of treatment oftreatment resistant depression.

Treatment of the above conditions may be beneficially improved by takingthe invention together with some complementary treatments; also thesetreatments may occur much less regularly than some other treatments thatrequire daily treatments or even multiple treatments a day.

For the sake of brevity only, various forms of the 5MeODMT benzoate saltmay be referred to herein below as ‘Pattern #’, wherein the # refers tothe corresponding XRPD pattern obtained for that form. For example‘Pattern A’ may be used as an abbreviation to refer to the form of5MeODMT benzoate salt giving rise to the Pattern A by XRPD. Likewise,‘Pattern B’ may be used as an abbreviation to refer to the form of5MeODMT benzoate salt giving rise to the Pattern B by XRPD, and so on.

The present invention will now be further described with reference tothe following, and the accompanying drawings, of which:

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic route for the synthesis of 5MeODMT.

FIG. 2 is a further schematic route for the synthesis of 5MeODMT.

FIG. 3 is a schematic route for the preparation of a powder form of5MeODMT.

FIG. 4 is an overview of the slug mucosal irritation (SMI) test. (A)First 15 minute contact period between slug and test item. (B) Slug istransferred onto a wet paper towel in a new Petri dish for 1 hour. (C)Second 15 minute contact period between slug and test item. (D) Slug istransferred onto a wet paper towel in a new Petri dish for 1 hour. (E)Third 15 minute contact period between slug and test item.

FIG. 5 is a graph showing that the benzoate salt of 5MeODMT has higherpermeation compared with the hydrochloride salt, as per the experimentdetailed in Example 9.

FIG. 6 shows an XRPD diffractogram of 5MeODMT benzoate prior to particlesize reduction.

FIG. 7 shows an XRPD diffractogram of 5MeODMT benzoate followingparticle size reduction.

FIG. 8 shows the XRPD diffractograms of FIGS. 6 and 7 overlaid on oneanother.

FIG. 9 shows a DSC thermograph of 5MeODMT benzoate.

FIG. 10 shows a TGA thermograph of 5MeODMT benzoate.

FIG. 11 shows a combined TGA/DSC thermograph of 5MeODMT benzoate.

FIG. 12 shows a DVS isotherm of 5MeODMT benzoate.

FIG. 12 shows a Dynamic Vapour Sorption (DVS) isotherm for 5MeODMTbenzoate.

FIG. 13 shows an optical micrograph of 5MeODMT benzoate salt (A) anddark field (B) at x4 magnification.

FIG. 14 shows two further optical micrographs of 5MeODMT benzoate salt(A) and (B) at x4 magnification.

FIG. 15 shows optical micrographs of 5MeODMT benzoate salt (A) and (B)at x10 magnification.

FIG. 16 shows further optical micrographs of 5MeODMT benzoate salt (A)and (B) at 10x magnification.

FIG. 17 shows a DVS isotherm of 5MeODMT hydrochloride (lot20/20/126-FP).

FIG. 18 shows a DVS isotherm of 5MeODMT hydrochloride (lot20/45/006-FP).

FIG. 19 shows XRPD pattern comparison of two different lots of 5MeODMTbenzoate.

FIG. 20 shows a DSC thermograph of another lot of 5MeODMT benzoate.

FIG. 21 shows additional XRPD characterisation of multiple lots of5MeODMT benzoate.

FIG. 22 shows DSC thermograph results for 5MeODMT benzoate lots C1, D1and E1.

FIG. 23 shows TGA thermograph results for 5MeODMT benzoate lots C1, D1and E1 at 10° C.min⁻¹.

FIG. 24 shows XRPD pattern comparison of 5MeODMT benzoate P1 (Toluene),Q1 (Chlorobenzene), and R1 (Anisole) against the XRPD pattern of PatternA.

FIG. 25 shows DSC thermographs of 5MeODMT lots P1, Q1 and R1 at 10°C.min⁻¹.

FIG. 26 shows DSC thermograph expansions of 5MeODMT lots P1, Q1 and R1at 10° C.min⁻¹.

FIG. 27 shows TGA thermographs of 5MeODMT lots P1, Q1 and R1 at 10°C.min⁻¹.

FIG. 28 shows XRPD pattern comparison of 5MeODMT benzoate lots R1 and R2(thermally cycled suspensions) compared with a reference Pattern A XRPDdiffractogram.

FIG. 29 shows DSC thermographs of 5MeODMT benzoate lots P2, Q2 and R2 at10° C.min⁻¹.

FIG. 30 shows DSC thermograph expansions of 5MeODMT benzoate lots P2, Q2and R2 at 10° C.min⁻¹.

FIG. 31 shows TGA thermographs of 5MeODMT benzoate lots P2, Q2 and R2 at10° C.min⁻¹.

FIG. 32 shows XRPD pattern overlay of samples isolated via anti-solventmediated crystallisation 5MeODMT benzoate.

FIG. 33 shows XRPD pattern overlay of 5MeODMT benzoate lot F1 and areference Pattern A form/material.

FIG. 34 shows XRPD pattern overlay of 5MeODMT benzoate samples isolatedfrom cooling and a Pattern A reference.

FIG. 35 shows XRPD pattern overlay of 5MeODMT benzoate samples isolatedfrom cooling post-particle size reduction and Pattern A reference.

FIG. 36 shows XRPD pattern comparison for all samples from the reverseaddition anti-solvent driven crystallisation of 5MeODMT benzoate exceptfor A1 and B1.

FIG. 37 shows XRPD pattern comparison for 5MeODMT benzoate F3 with aknown Pattern A reference.

FIG. 38 shows XRPD pattern comparison of 5MeODMT benzoate A1 and B1.

FIG. 39 shows XRPD patterns for 5MeODMT benzoate A1, Q1 and a referencePattern A pattern.

FIG. 40 shows XRPD patterns for 5MeODMT benzoate B1, Q1 and a referencePattern A pattern.

FIG. 41 shows a DSC thermograph of 5MeODMT benzoate sample A1 at 10°C.min⁻¹ isolated from methanol and toluene.

FIG. 42 shows a DSC thermograph of 5MeODMT benzoate B1 at 10° C.min-1isolated from isopropanol and toluene.

FIG. 43 shows a DSC thermograph expansion of 5MeODMT benzoate. B1 at 10°C.min-1 isolated from isopropanol and toluene.

FIG. 44 shows XRPD comparison of 5MeODMT benzoate lot 21-01-051 A, E; EParticle size reduced and Pattern A reference.

FIG. 45 shows XRPD of 5MeODMT benzoate lot 21-01-051 B, obtained fromquenching the melt.

FIG. 46 shows XRPD of 5MeODMT benzoate lot 21-01-051 C, obtained bylyophilisation.

FIG. 47 shows XRPD comparison of 5MeODMT benzoate lot 21-01-051 B after20 hours, C after 20 hours, and Pattern A reference.

FIG. 48 shows XRPD comparison of 5MeODMT benzoate lot 21-01-051 A, E; Eparticle size reduced, and Pattern A reference.

FIG. 49 shows DSC thermograph comparison of 5MeODMT benzoate lot21-01-051 A, C, and D at 10° C.min⁻¹, isolated from acetone concentrate,051 A, and lyophilisation, 051 C and 051 D.

FIG. 50 shows DSC thermograph comparison of 5MeODMT benzoate lot21-01-051 C and C post 20 hours at 10° C.min⁻¹.

FIG. 51 shows DSC thermograph of 5MeODMT benzoate lot 21-01-051 D, largescale lyophilised material, with temperature stamps corresponding tohot-stage microscopy images.

FIG. 52 shows Micrograph image of 5MeODMT benzoate lot 21-01-051 D at30.02° C.

FIG. 53 shows Micrograph image of 5MeODMT benzoate lot 21-01-051 D at54.21° C.

FIG. 54 shows Micrograph image of 5MeODMT benzoate lot 21-01-051 D at74.21° C.

FIG. 55 shows Micrograph image of 5MeODMT benzoate lot 21-01-051 D at114.23° C.

FIG. 56 shows Micrograph image of 5MeODMT benzoate lot 21-01-051 D at120.14° C.

FIG. 57 shows XRPD pattern comparison of 5MeODMT benzoate lot 21-01-054solids isolated from the equilibration of amorphous 5MeODMT benzoatewith thermal modulation.

FIG. 58 shows XRPD pattern comparison of 5MeODMT benzoate lot 21-01-054M isolated from the equilibration of amorphous 5MeODMT benzoate inα,α,α-trifluorotoluene with thermal modulation with lot 20-37-64(Pattern A).

FIG. 59 shows DSC thermograph comparison of a selection of 5MeODMTbenzoate lot 21-01-054 solids isolated from the equilibration ofamorphous 5MeODMT benzoate with thermal modulation classified as PatternA.

FIG. 60 shows DSC thermograph expansion comparison of 5MeODMT benzoatelot 21-01-054 solids isolated from the equilibration of amorphous5MeODMT benzoate with thermal modulation classified as Pattern A,highlighting an event in lot 21-01-054 Q, solid isolated from anisole.

FIG. 61 shows Expanded DSC thermograph expansion highlighting an eventin lot 21-01-054 Q, isolated from anisole.

FIG. 62 shows XRPD pattern comparison of 5MeODMT benzoate lot 21-01-060A1 air dried 2 minutes, lot 21-01-049 B1, Pattern B, and lot 20-37-64,Pattern A.

FIG. 63 shows XRPD pattern comparison of 5MeODMT benzoate lot 21-01-060A1-air dried 1 hour and lot 21-01-060 A1-air dried 2 minutes.

FIG. 64 shows XRPD pattern comparison of 5MeODMT benzoate lot 21-01-060A1-air dried 2 minutes, lot 21-01-060 A1-air dried 1 hour, and lot21-01-049 B1, Pattern B.

FIG. 65 shows DSC thermograph of 5MeODMT benzoate lot 21-01-060 A1,isolated immediately from IPA/toluene and air dried for 1 hour.

FIG. 66 shows DSC thermograph expansion of 5MeODMT benzoate lot21-01-060 A1, isolated immediately from IPA/toluene and air dried for 1hour.

FIG. 67 shows XRPD pattern comparison of 5MeODMT benzoate lot 21-01-060A1 air dried 20 hours, lot 21-01-060 A1 air dried 2 minutes, and lot21-01-049 B1, Pattern B reference.

FIG. 68 shows XRPD pattern comparison of 5MeODMT benzoate lot 21-01-060B1, isolated after 3 hours equilibration then air dried for 2 mins andA1 isolated immediately then air dried for 2 minutes.

FIG. 69 shows XRPD pattern comparison of 5MeODMT benzoate lot 21-01-060B1, isolated after 3 hours equilibration then air dried for 20 hours andB1 isolated after 3 hours equilibration then air dried for 2 minutes,and lot 21-01-049 B1, Pattern B.

FIG. 70 shows XRPD pattern comparison of 5MeODMT benzoate lot 21-01-058solids isolated from amorphous 5MeODMT benzoate exposed to solventvapour.

FIG. 71 shows XRPD pattern comparison of 5MeODMT benzoate lot 21-01-058K, isolated from amorphous 5MeODMT benzoate exposed to solvent vapour,with lot 20-37-64, Pattern A.

FIG. 72 shows DSC thermograph comparison of 5MeODMT benzoate lot21-01-058 B, lot 21-01-058 F, lot 21-01-058 K, and lot 21-01-062 G.

FIG. 73 shows XRPD pattern comparison of 5MeODMT benzoate lot 21-01-058D, lot 20-37-64, Pattern A, lot 21-01-049 B1, Pattern B, and lot21-01-060 B1, Pattern C (air dried 20 hours).

FIG. 74 shows XRPD pattern comparison of 5MeODMT benzoate lot 21-01-058D, lot 21-01-049 B1, Pattern B, and lot 21-01-060 B1, Pattern C (airdried 20 hours).

FIG. 75 shows XRPD pattern expansion comparison of 5MeODMT benzoate lot21-01-058 D, lot 21-01-049 B1, Pattern B, and lot 21-01-060 B1, PatternC (air dried 20 hours).

FIG. 76 shows DSC thermograph of 5MeODMT benzoate lot 21-01-058 D,isolated from exposure of anisole vapour to amorphous form.

FIG. 77 shows XRPD pattern comparison of 5MeODMT benzoate lot 21-01-064D, and 21-01-060 B1 (air dried 2 minutes).

FIG. 78 shows XRPD pattern expansion comparison of 5MeODMT benzoate lot21-01-064 D, and 21-01-060 B1 (air dried 2 minutes).

FIG. 79 shows DSC thermograph of 5MeODMT benzoate lot 21-01-064 D at 10°C.min-1.

FIG. 80 shows XRPD pattern comparison of 5MeODMT benzoate lot 21-01-064C, and 21-01-064 D.

FIG. 81 shows XRPD pattern expansion comparison of 5MeODMT benzoate lot21-01-064 C, and 21-01-064 D.

FIG. 82 shows DSC thermograph of 5MeODMT benzoate lot 21-01-064 C at 10°C.min-1.

FIG. 83 shows XRPD pattern comparison of 5MeODMT benzoate lot 21-01-073A, 21-01-049 B1, Pattern B, and 20-37-64, Pattern A.

FIG. 84 shows XRPD pattern comparison of 5MeODMT benzoate lot 21-01-073F and 21-01-073 F rerun.

FIG. 85 shows XRPD pattern comparison of 5MeODMT benzoate lot 21-01-073F rerun, 21-01-049 B1, Pattern B, and 20-37-64, Pattern A.

FIG. 86 shows XRPD pattern expansion comparison of 5MeODMT benzoate lot21-01-073 F rerun, 21-01-049 B1, Pattern B, and 20-37-64, Pattern A.

FIG. 87 shows XRPD pattern comparison of 5MeODMT benzoate lot 21-01-073K, 21-01-049 B1, Pattern B, and 20-37-64.

FIG. 88 shows XRPD of 5MeODMT benzoate lot 21-01-078.

FIG. 89 shows DVS isothermal plot of 5MeODMT benzoate lot 21-01-078.

FIG. 90 shows XRPD pattern comparison of 5MeODMT benzoate lot 21-01-078(post-DVS) and 20-37-64.

FIG. 91 shows FTIR overlay of 5MeODMT benzoate Pattern A form(20-20-150FP2), Pattern B form (21-01-071 C2) and Pattern C form(21-010071 C1).

FIG. 92 shows FTIR overlay of 5MeODMT benzoate Pattern A form(20-20-150FP2), Pattern B form (21-01-071 C2) and Pattern C form(21-010071 C1) at 450 to 2000 cm-1.

FIG. 93 shows FTIR overlay of 5MeODMT benzoate Pattern A form(20-20-150FP2), Pattern B form (21-01-071 C2) and Pattern C form(21-010071 C1) at 450 to 2000 cm-1; spectra separated.

FIG. 94 shows Forced Swim Test results, Time Immobile, for 5MeODMTbenzoate, vehicle and imipramine.

FIG. 95 shows Forced Swim Test results, Latency to Immobility, for5MeODMT benzoate, vehicle and imipramine.

FIG. 96 shows 5MeODMT Group Mean Plasma Concentration (ng/mL) in MaleBeagle Dogs - Group 2 (HCl salt) and Group 4 (benzoate salt) - DoseLevel (0.4 mg/kg); wherein the Mean Plasma Concentration of Groups 2 and4 are substantially the same with dose time.

DETAILED DESCRIPTION OF THE INVENTION

FIG. 1 shows a one-step synthesis of 5MeODMT from the reaction of4-methoxyphenylhydrazine hydrochloride with (N,N)-dimethylamino)butanaldimethyl acetal.

FIG. 2 shows a three step synthesis of 5MeODMT. The first step involvesthe reaction of 5-methoxyindole with oxalyl chloride. The resultantproduct is aminated with dimethylamine and then is reduced with lithiumaluminium hydride.

FIG. 3 shows the schematic route for the formation of a powder form of5MeODMT using a spray drying process.

EXAMPLES Example 1: Synthesis of 5MeODMT (the Free Base) in on Step (theFree Base)

A schematic representation of this reaction is shown in FIG. 1 .

Hydrazine (1.0 eq), diethyl acetal (1.2 eq), and aqueous sulfuric acid(0.1 eq) where heated together at 65-75° C. for 18 hours. MTBE (10 vol)was added, followed by adjustment to about pH10 using 12% caustic (about1.1eq.). The layers were separated and the aqueous fraction backextracted with MTBE (10vol). The combined organic fractions were washedwith water (10vol) twice, then evaporated to dryness under vacuum. Yield100%.

Example 2: Synthesis of 5MeODMT (the Free Base) in Three Steps

A schematic representation of this reaction is shown in FIG. 2 .

Step 1 - Add methyl tert-butyl ether (MTBE) (15vol) into the reactionvessel and cool to -20 to -30° C., before adding oxalyl chloride (1.5eq), maintaining the temperature at no more than -20° C. Add a solutionof 5-methoxyindole (1.0eq) in THF (1vol) to the reaction vessel,maintaining the temperature at no more than -20° C. Allow the reactionto warm to 0-5° C. and stir for at least 1 hour, ensuring that no morethan 2% of the starting material indole remains.

Cool the reaction to between -20 to -30° C. and add a solution ofmethanol (1vol) and MTBE (1vol), maintaining the temperature at no morethan -20° C. Allow the reaction to warm to 0-5° C. over no less than 30minutes and stir for at least 1 hour.

Filter and wash the solids with MTBE cooled to 0-5° C. Add the washedfiltered solids and methanol (20vol) to a reaction vessel. Heat to60-65° C. and stir for no more than 30 minutes. Cool to 0-5° C. over noless than 2 hours and stir for no less than 2 hours. Filter and wash thesolids with MTBE cooled to 0-5° C. Dry the solids obtained at no morethan 40° C. for no less than 12 hours. Yield 95%.

Step 2 – Add the compound obtained in step 1 (1.0 eq) to a reactionvessel together with dimethylamine hydrochloride (3.0 eq) and methanol(2vol). Add 25% NaOMe in methanol (3.5 eq), to the reaction maintainingthe temperature at no more than 30° C. Warm to and stir for no less than5 hours, ensuring that no more than 0.5% of the starting material fromstep 1 remains. Adjust the temperature to 0-5° C. over no less than 2hours, then add water (5vol) over no less than 1 hour with stirring at0-5° C. for no less than 1 hour.

Filter and wash the solids with water cooled to 0-5° C., and dry thesolids obtained at no more than 40° C. for no less than 12 hours. Yield85%.

Step 3 – Add the compound obtained in step 2 (1.0 eq) to a reactionvessel. Add 1M LiAlH4 in THF (1.5 eq) in THF (8vol) to the reactionmaintaining no more than 40° C. Heat at reflux for no less than 4 hoursensuring that no more than 2% of the starting material from step 2remains.

Adjust to 0-5° C. and add water (0.25vol) in THF (0.75vol) over no lessthan 30 minutes, maintaining no more than 10° C. Then add 15% caustic(0.25vol) maintaining the temperature at no more than 10° C. Add water(0.65vol) maintaining the temperature at no more than 10° C. Add THF(0.25vol) as a vessel rinse and stir the contents at 0-5° C. for no lessthan 30 minutes. Add sodium sulfate (100 wt%) and stir contents at 0-5°C. for no less than 30 minutes.

Filter and wash the solids with toluene (2×10vol) and keep liquorsseparate. Recharge THF liquors to a clean vessel and distil under vacuumto minimum stir. Charge toluene liquors and distil under vacuum to about10vol. Then add water (5vol) and stir for no less than 15 minutes. Stop,settle and remove aqueous layer to waste. Charge with 4% HCl to a pH ofbetween 1-2 (about 4vol) and stir for no less than 15 minutes. Stop,settle and remove organic layer to waste. Charge MTBE (15vol). Chargewith 15% caustic to a pH between 11-13 (about 0.9vol). Stir for no lessthan 15 minutes. Stop, settle and remove aqueous layer to waste. Chargewith water (5vol). Stir for no less than 15 minutes. Stop, settle andremove the aqueous layer to waste.

Example 3: Synthesis of 5MeODMT Hydrochloride Salt

5MeODMT (the free base) is dissolved in toluene (1.0 to 2.5vol).Isopropyl alcohol (IPA) was then added (2.5vol) followed by 1.25M HCl inIPA (1.0 eq) and the temperature adjusted to 0-5° C. over 1 hour.

If no precipitation/crystallization occurs, toluene (6.25vol) is addedover 30 minutes. The mixture was then stirred at 0-5° C. for 2 hours.The resultant solid is filtered, washed with toluene (3.8vol). The solidwas dried under vacuum at ambient temperature. Yield 58%.

Example 4: Synthesis of 5MeODMT Benzoate Salt

5MeODMT (the free base) is dissolved in toluene (1 eq) and benzoic acid(1 eq) in toluene (10vol) is added over a period of 20 minutes andstirred at room temperature for 2 hours. The resultantprecipitation/crystallization was filtered and washed with toluene(2.5vol) and dried under vacuum at room temperature.

Isopropyl acetate (IPAc) (15.8vol) was added to the solids obtainedabove and the temperature was raised to about 73° C. until the soliddissolved. The solution was allowed to cool to 0-5° C. over 2 hours andthis temperature was maintained for 1 hour with stirring. The resultantbenzoate salt was filtered and vacuum dried at room temperature. Yield68%.

Example 5: Synthesis of 5MeODMT Fumarate Salt

5MeODMT (the free base) is added to a solution of fumaric acid (0.5 eq)in IPA over 15 minutes at 40-45° C. The resultant solution was cooled atroom temperature and stirred for 16 hours. The solution was then cooledto 0-5° C. with stirring for 2 hours. The resultingprecipitation/crystallization was filtered and was rinsed with toluene(2.5vol). Yield 68%.

Example 6: 5MeODMTpowder

A schematic route for the preparation of a powder form of 5MeODMT (orthe salt thereof) is shown in FIG. 3 . The three main steps in theprocess are:

-   1. Spray drying a solution containing the substance(s) of interest    (e.g. 5MeODMT, or the salt, thereof inclusive of any excipients).    This can be done via an atomizing nozzle such as with rotary    atomizers, pressure atomizers, twin fluid nozzles, ultrasonic    atomizers, four-fluid nozzles. This is done so as to form droplets    capable of generating co-formed particles in the desired particle    size range.-   2. Drying of the atomized droplets (e.g. with nitrogen gas,    optionally at an elevated temperature).-   3. Separating and collecting the dried particles from the gas stream    (e.g. using a cyclone separator to capture the required size    fraction).

Example 7: Slug Mucosal Irritation Assay

The Slug Mucosal Irritation (SMI) assay was initially developed at theLaboratory of Pharmaceutical Technology (UGent) to predict the mucosalirritation potency of pharmaceutical formulations and ingredients. Thetest utilizes the terrestrial slug Arion lusitanicus. The body wall ofthe slugs is a mucosal surface composed of different layers. The outersingle-layered columnar epithelium that contains cells with cilia, cellswith micro-villi and mucus secreting cells covers the subepithelialconnective tissue. Slugs that are placed on an irritating substance willproduce mucus. Additionally tissue damage can be induced which resultsin the release of proteins and enzymes from the mucosal surface. Severalstudies have shown that the SMI assay is a useful tool for evaluatingthe local tolerance of pharmaceutical formulations and ingredients. Aclassification prediction model that distinguishes between irritation(mucus production) and tissue damage (release of proteins and enzymes)has been developed. Furthermore, several studies with ophthalmicpreparations have shown that an increased mucus production is related toincreased incidence of stinging, itching and burning sensations. In 2010a clinical trial was set up to evaluate the stinging and burningsensations of several diluted shampoos. A 5% shampoo dilution orartificial tears were instilled in the eye and the discomfort was scoredby the participants on a 5 point scale during several time points up to30 min after instillation. The same shampoos were tested in the SMIassay using the Stinging, Itching and Burning (SIB) protocol. This studyshowed that an increased mucus production was related with an increasedincidence of stinging and burning sensations in the human eye irritationtest. The relevance of the assay to reliably predict nasal irritationand stinging and burning sensations was demonstrated using several OTCnasal formulations, isotonic, and hypertonic saline.

Furthermore, the test was validated using reference chemicals for eyeirritation (ECETOC eye reference data bank). These studies have shownthat the SMI assay can be used as an alternative to the in vivo eyeirritation tests. Moreover, a multi-center prevalidation study with fourparticipating laboratories showed that the SMI assay is a relevant,easily transferable and reproducible alternative to predict the eyeirritation potency of chemicals.

The purpose of this assay was to assess the stinging, itching or burningpotential of the test item(s) defined below. Using the objective valuesobtained for the mucus production the stinging, itching or burningpotential of the test item(s) can be estimated by means of theprediction model that is composed of four categories (no, mild, moderateand severe).

Control Items:

-   Negative control - Name: Phosphate buffered saline (PBS)-   Positive control - Name: 1% (w/v) Benzalkonium chloride in PBS

Test items:

-   Compound 1    -   Name: 10% (w/v) Disodium fumarate in PBS    -   CASRN: 17013-01-3    -   Batch: KBSJ-P0    -   Description: colourless solution    -   Storage condition: room temperature (compounded on the day of        the experiment)-   Compound 2    -   Name: 10% (w/v) Sodium phosphate monobasic in PBS    -   CASRN: 7558-80-7    -   Batch: 2A/220991    -   Description: colourless solution    -   Storage condition: room temperature (compounded on the day of        the experiment)-   Compound 3    -   Name: 10% (w/v) Sodium acetate in PBS    -   CASRN: 127-09-3    -   Batch: 5A/233258    -   Description: colourless solution    -   Storage condition: room temperature (compounded on the day of        the experiment)-   Compound 4    -   Name: 10% (w/v) Sodium citrate in PBS    -   CASRN: 68-04-2    -   Batch of vial: 5A/241516    -   Description: colourless solution    -   Storage condition: room temperature (compounded on the day of        the experiment)

Test System: Slugs (Arion lusitanicus); 3 slugs per treatment group. Theparental slugs of Arion lusitanicus collected in local gardens alongGent and Aalter (Belgium) are bred in the laboratory in an acclimatizedroom (18-20° C.). The slugs are housed in plastic containers and fedwith lettuce, cucumber, carrots and commercial dog food.

Test Design: A single study was performed. Treatment time was 15 minutesthree times on the same day.

Preparation of Slugs:

Slugs weighing between 3 and 6 g were isolated from the cultures twodays before the start of an experiment. The body wall was inspectedcarefully for evidence of macroscopic injuries. Only slugs with cleartubercles and with a foot surface that shows no evidence of injurieswere used for testing purposes. The slugs were placed in a plastic boxlined with paper towel moistened with PBS and were kept at 18 - 20° C.Daily the body wall of the slugs was wetted with 300 µl PBS using amicropipette.

Test Procedure:

The stinging, itching or burning potency of the test item(s), wasevaluated by placing 3 slugs per treatment group 3 times a day on 100 µLof test item in a Petri dish for 15 ± 1 min. After each 15-min contactperiod the slugs were transferred for 60 min into a fresh Petri dish onpaper towel moistened with 1 mL PBS to prevent desiccation. An overviewof this can be seen in FIG. 4 .

Mucus Production:

The amount of mucus produced during each contact period was measured byweighing the Petri dishes with the test item before and after each15-min contact period. The mucus production was expressed as % of thebody weight. The slugs were weighed before and after each 15-mincontact.

Classification Prediction Model

Based on the endpoint of the SMI assay the stinging, itching or burningpotency of the test item(s) was estimated using a classificationprediction model.

The evaluation of the test results was based upon the total amount ofmucus production during 3 repeated contact periods with the test item.

For each slug, the mucus production was expressed in % of the bodyweight by dividing the weight of the mucus produced during each contactperiod by the body weight of the slug before the start of that contactperiod. The total mucus was calculated for each slug and then the meanper treatment group was calculated. The classification prediction modelshown in Table 1 was used to classify the compounds.

TABLE 1 Cut-off values for classification - potency for nasal mucosaldiscomfort Total Mucus production in % (mean of n = 3) Stinging, Itchingand Burning (SIB) < 5.5% No ≥ 5.5 and < 10% Mild ≥ 10 and < 17.5%Moderate ≥ 17.5% Severe

Acceptance Criteria

Before a test was considered valid, the following criteria must be met:

-   the negative control should be classified as causing no stinging,    itching and burning (Total mucus production < 5.5%)-   the positive control item should be classified as causing severe    stinging, itching and burning (Total mucus production ≥ 17.5%)

Irritation Potential

TABLE 2 Amount of mucus produced (MP) during each 15-min contact period(CP) and total amount of mucus produced Formulation MP CP1¹ (%) MP CP2¹(%) MP CP3¹ (%) Total MP¹ (%) SIB Category² NC – PBS -0.2 ± 0.3 -0.6 ±0.1 0.3 ± 0.6 -0.5 ± 0.7 No PC – 1% BAC 9.2 ± 1.5 8.4 ± 1.2 5.9 ± 3.123.4 ± 3.6 Severe Disodium fumarate, 10% 5.0 ± 2.5 4.7 ± 1.7 3.6 ± 0.813.3 ± 1.8 Moderate Sodium phosphate, 10% monobasic 3.3 ± 0.9 5.6 ± 0.36.2 ± 1.3 15.2 ± 1.8 Moderate Sodium acetate, 10% 3.3 ± 0.2 3.9 ± 0.43.9 ± 0.2 11.0 ± 0.8 Moderate Sodium citrate, 10% 4.2 ± 0.5 4.2 ± 0.34.1 ± 1.1 12.5 ± 1.4 Moderate NC: negative control; PC: positivecontrol; BAC: benzalkonium chloride ¹Mean ± SD, n=3 ² No: total MP <5.5%; Mild: 5.5% ≤ total MP < 10%; Moderate: 10% ≤ total MP < 17.5%;Severe: total MP ≥ 17.5%

The average amount of mucus produced during each 15-min contact periodand total mucus production (total MP) is presented in Table 2. Accordingto the classification prediction model of the SMI test, the negativecontrol (untreated slugs) did not induce reactions in the slugs (meantotal MP < 5.5%). The positive control on the other hand (DDWM/SLS80/20) induced a high mucus production during each contact period (meantotal MP ≥ 17.5%) resulting in a classification as severe stinging,itching, and burning (SIB) reactions. The acceptance criteria were metand the experiment was considered valid.

In total, 4 different solutions were tested. The amount of mucusproduced during each 15-min contact period was between 10% and 17.5%,indicating moderate SIB reactions. The test items can be rankedaccording to increasing total mucus production: sodium acetate (10% w/v)< sodium citrate (10% w/v) < disodium fumarate (10% w/v) < sodiumphosphate (10% w/v).

Numerical Data

Treatment Replicate MP CP1 MP CP2 MP CP3 Total MP NC 1 -0.32 -0.59 0.970.06 2 -0.44 -0.57 -0.32 -1.33 3 0.14 -0.70 0.35 -0.21 PC 1 8.08 7.919.29 25.28 2 10.82 9.71 5.23 25.77 3 8.59 7.49 3.17 19.25 Disodiumfumarate, 10% 1 7.83 3.56 3.14 14.53 2 4.39 6.64 3.11 14.14 3 2.87 3.844.47 11.17 Sodium phosphate, 10% monobasic 1 4.33 5.34 7.41 17.07 2 2.935.69 6.40 15.02 3 2.74 5.83 4.89 13.46 Sodium acetate, 10% 1 3.47 4.244.10 11.80 2 3.44 3.93 3.81 11.18 3 3.06 3.43 3.69 10.17 Sodium citrate,10% 1 4.16 4.01 3.78 11.95 2 4.75 4.03 5.33 14.12 3 3.68 4.55 3.25 11.48

TABLE 3 Amount of mucus produced (MP) during each 15-min contact period(CP) and total amount of mucus produced Formulation MP CP1¹ (%) MP CP2¹(%) MP CP3¹ (%) Total MP¹ (%) SIB Category² NC – PBS -0.2 ± 0.3 -0.6 ±0.1 0.3 ± 0.6 -0.5 ± 0.7 No PC – 1% BAC 9.2 ± 1.5 8.4 ± 1.2 5.9 ± 3.123.4 ± 3.6 Severe Disodium fumarate, 10% 5.0 ± 2.5 4.7 ± 1.7 3.6 ± 0.813.3 ± 1.8 Moderate Sodium phosphate, 10% monobasic 3.3 ± 0.9 5.6 ± 0.36.2 ± 1.3 15.2 ± 1.8 Moderate Sodium acetate, 10% 3.3 ± 0.2 3.9 ± 0.43.9 ± 0.2 11.0 ± 0.8 Moderate Sodium citrate, 10% 4.2 ± 0.5 4.2 ± 0.34.1 ± 1.1 12.5 ± 1.4 Moderate NC: negative control; PC: positivecontrol; BAC: benzalkonium chloride ¹Mean ± SD, n=3 ² No: total MP <5.5%; Mild: 5.5% ≤ total MP < 10%; Moderate: 10% ≤ total MP < 17.5%;Severe: total MP ≥ 17.5%

TABLE 4 Amount of mucus produced (MP) during each 30-min contact period(CP) and total amount of mucus produced (Code 00E04) Treatment CP130-min CP2 30-min Total MP PBS -1.0 ± 0.6 -1.1 ± 0.8 -2.2 ± 0.6 BAC (1%)13.2 ± 4.2 18.6 ± 9.8 31.8 ± 12.6 Sodium oxalate (1%) 4.5 ± 1.3 6.6 ±1.0 11.1 ± 2.0

TABLE 5 Amount of mucus produced (MP) during each 60-min contact period(CP) and total amount of mucus produced Treatment Day 1 CP1 60-min Day 2CP2 60-min Total MP PBS -0.2 ± 0.7 -0.7 ± 0.5 -0.9 ± 0.5 BAC (1% CP1 &3.5% CP2) 21.9 ± 4.8 9.7 ± 3.2 31.6 ± 2.5 Sodium oxalate (1% CP1 & 3.5%CP2) 11.2 ± 3.9 16.0 ± 4.0 27.1 ± 2.3

TABLE 6 Amount of mucus produced (MP) during a 60-min contact period(CP) Treatment CP1 60-min PBS -0.2 ± 1.0 BAC (1%) 15.0 ± 1.9 Sodiumbenzoate (1%) 2.6 ± 0.3 Sodium benzoate (10%) 6.9 ± 1.2

Results

The total MP for a 60-min treatment (historical data) was compared withthe total MP of the SIB protocol (3× 15-min treatment; current data). Inthe table below a ranking is proposed from least SIB reactions tohighest SIB reactions:

Compound Concentration Treatment time Total MP (% body weight) Sodiumbenzoate 1% 60-min 2.6 Sodium benzoate 10% 60-min 6.9 Sodium acetate 10%45-min (3x 15-min) 11.0 Sodium citrate 10% 45-min (3x 15-min) 12.5Disodium fumarate 10% 45-min (3x 15-min) 13.3 Sodium phosphate 10%45-min (3x 15-min) 15.2 Sodium oxalate 1% 60-min 11.2

Sodium oxalate appears to be the most irritating salt since a 1%concentration results in 11.2% total MP after 1 hour of contact. Sodiumbenzoate is the least irritating salt.

Example 8: Further Slug Mucosal Irritation (SMI) Testing

5MeODMT as a freebase compound is known to be highly irritating to themucosal lining; therefore, it is commonly prepared as a salt forinsufflation. The hydrochloride (HCl) salt of 5MeODMT is most commonlyused due to ease of crystallisation. However, it is known that the HClsalt of 5MeODMT is still quite irritating to the mucosal lining.

Following the results above indicating that sodium benzoate is the leastirritating salt of those studied; further SMI testing was performed on5MeODMT benzoate and the common 5MeODMT HCl salt according to thepreviously described methods (of Example 7). The results of this areshown below:

Compound Concentration (w/v) Total MP (% body weight) 5MeODMT benzoate10% 7.38 5MeODMT HCl 10% 10.27 Benzylkonium (positive control) 10% 17.56PBS (negative control) 10% -0.77

The 5MeODMT benzoate produced ‘mild’ irritation compared to the 5MeODMTHCl which scored as ‘moderate’ on testing.

Example 9: Permeation Data

The use of ovine nasal epithelium to study nasal drug absorption is atechnique which is well known to the person skilled in the art.

The permeation of 5MeODMT benzoate and 5MeODMT HCl has been studied bythe current applicants. Dosing solutions corresponding to 1.25%concentration were prepared in water and applied to ovine nasalepithelium. The average cumulative (µg/cm²) of permeation of thebenzoate and hydrochloride salt are shown in the table below (mean ± SD,n=5):

Time (min) 0.0 10.0 20.0 30.0 40.0 50.0 60.0 75.0 90.0 Cumulative amount(µg/cm² (SD)) 5-MeO-DMT Benzoate 0.00 (0.00) 0.20 (0.35) 3.46 (3.07)9.30 (6.46) 15.46 (10.00) 21.51 (11.42) 27.30 (13.73) 33.34 (14.80)39.77 (14.81) 5-MeO-DMT Hydrochloride 0.00 (0.00) 0.33 (0.52) 3.30(3.51) 8.26 (6.70) 13.33 (8.58) 18.77 (10.75) 23.43 (11.38) 29.52(12.77) 35.36 (13.29)

The cumulative amount of 5MeODMT benzoate and 5MeODMT hydrochloridewhich permeated through ovine nasal epithelium per unit area followingapplication of 1.25% dosing solutions prepared in water (mean ± SD, n=5)can be seen in FIG. 5 .

As can clearly be seen, the benzoate salt has higher permeation acrossthe epithelium.

The above data obtained in the above test show that the 5MeODMT benzoatesalt gives higher permeation with less mucosal irritation than thecommonly used HCl salt; and so this combination of properties makes thebenzoate salt an ideal candidate for mucosal delivery. For example, less5MeODMT benzoate salt may be needed by inhalation to provide the samebenefit as the HCl salt and the benzoate salt is less irritating, and soprovides a synergistic benefit. Smaller amounts of compound also makeinhalation easier to accomplish.

Example 10: Effects on the Central Nervous System Function

In the following examples, BPL-5MEO refers to5-methoxy-N,N-dimethyltryptamine (5MeODMT).

In the following examples, the hydrochloride salt of 5MeODMT was used.

The following Examples (10-14) summarizes applicant-sponsored safetypharmacology studies to assess the effects of BPL-5MEO on CNS,cardiovascular system, and respiratory system function. The studydesigns are based on in the International Council for Harmonisation(ICH) S7A/B Guidance and were conducted in compliance with GLPregulations.

The pharmacological effects of BPL-5MEO on CNS function was assessedusing a Functional Observational Battery (FOB) in male Sprague-Dawleyrats following a single intranasal administration (ITR study 15951).

The test and control/vehicle items were administered by single doseintranasal administration to both nostrils, as shown in Table 7.

TABLE 7 Experimental Design of Study 15951 Group No. Group Designation aDose Level (mg/kg) Dose Concentration (mg/mL) Dose Volume c (µL/kg) No.of Male Animals 4 Control b 0 0 75 Right Nostril + 75 Left Nostril 6 3Low Dose 1.5 10 6 2 Mid Dose 3 20 6 1 High Dose 10 66.67 6 a Theobservers performing the FOB were not aware of the specific treatmentadministered to the animals. b Control animals were administered 0.1%hydroxypropyl methyl cellulose (HPMC) in water. c Dose volume did notexceed 25 µL/nostril for all animals regardless of their bodyweight.

Parameters monitored included mortality and clinical signs. Generalbehavioral changes were assessed using FOB at 6 timepoints: beforedosing, and at 15 minutes, 1, 2, 4, and 24 hours postdosing. On eachoccasion, the FOB was performed at 4 stages: when the animals were intheir home cage, while handling the animals, when the animals werefreely moving in an open-field, and when they received diverse stimulifor reactivity evaluation. The body temperature and neuromuscularstrength were also measured on each of the occasions detailed above.

The FOB examinations were grouped according to functional domains of thenervous system as shown in Table 8.

TABLE 8 Functional Domains of the Nervous System and AssociatedObservations Domain Behavioral Observations Performed Behavioral Postureand activity in home cage/bin Ease of removal from the cage/bin Handlingreactivity Arousal Rearing Exploratory activity Touch response Abnormalor stereotyped behavior Neurological (sensorimotor) / NeuromuscularVision test Touch response Auditory test Tail pinch response Eye blinkresponse Flexor reflex Extensor thrust reflex Pinna reflexProprioceptive positioning Righting reaction Hindlimb foot splayInvoluntary motor movements (such as convulsion and tremors) GaitForelimb and hindlimb grip strength Autonomic Lacrimation SalivationPupil response to light Palpebral closure Defecation UrinationPiloerection Exophthalmos Body temperature

There was no treatment-related mortality/morbidity. TransientBPL-5MEO-related clinical signs were noted immediately following dosingand consisted mainly of decreased activity, lying on the cage floor,shallow/increased respiration and dilated pupils at all dose groups.Tremors, salivation, and gasping were observed in some animals at the 3and 10 mg/kg doses, and twitching was noted in one animal at 10 mg/kg.

In the behavioral domain of the FOB, a single intranasal administrationof BPL-5MEO at doses of 1.5, 3, and 10 mg/kg resulted in transientdecreased activity, lying on the cage floor, and decreased rearing at 15minutes postdose. All behavioral parameters were comparable to controlanimals at 1-hour postdose.

In the neurological (sensorimotor) /neuromuscular domain of the FOB, asingle intranasal administration of BPL-5MEO at 1, 5, and 10 mg/kgresulted in transient changes in gait (difficulty in movement) at alldose levels. All neurological (sensorimotor) /neuromuscular parameterswere comparable to control animals at 1-hour postdose.

In the autonomic domain, a single intranasal administration of BPL-5MEOof 1, 5, and 10 mg/kg was associated with salivation, piloerection,increased respiration, dilated pupils and changes in body temperaturewas noted across all dose levels. All autonomic parameters werecomparable with control animals at 2 hours postdose.

In conclusion, the single intranasal administration of BPL-5MEO at dosesof 1.5, 3, and 10 mg/kg resulted in transient clinical signs, consistentwith observable changes in behavior, neurological (sensorimotor)/neuromuscular and autonomic parameters which were fully resolved within1 or 2 hours following dosing.

Example 11: Effects on Cardiovascular Function In Vitro Study

The in vitro effect of 5MeODMT on the hERG potassium channel current(I_(Kr)), the rapidly activating, delayed rectifier cardiac potassiumcurrent, was assessed using the patch clamp technique in stablytransfected human embryonic kidney (HEK-293) cells that expressed thehERG gene (CRL study 1020-5458). This assay is employed as a screen toassess potential risks for QT interval prolongation.

The study was conducted in 2 phases: Phase 1 assessed the onset andsteady-state inhibition of hERG at a selected concentration of 30 µm5MeODMT; Phase 2 assessed the concentration response if the results fromPhase 1 showed inhibition of 20% or more. The initial concentration of30 µm was selected based on the results of an exploratory dose-rangefinding study in dogs, where intranasal administration of 2.5 mg/kgBPL-5MEO resulted in a mean C_(max) of 803 ng/mL (3.67 µM) 5MeODMT. Asolution of 30 µM used in Phase 1 provided an 8-fold margin over thisconcentration.

In Phase 1, the 30 µM concentration of 5MeODMT in protein free perfusateinhibited hERG potassium ion current by 77.8 ± 7.4% (n=3). Therefore,Phase 2 was undertaken using concentrations of 1, 3, 10, and 35 µm5MeODMT in protein free perfusate (corresponding to 0.2, 0.6, 2.0, and7.2 µg/mL of unbound drug substance).

In Phase 2, 5MeODMT inhibited hERG potassium ion channel current in aconcentration-dependent manner as presented in Table 9.

TABLE 9 Mean Percent Inhibition of hERG Potassium ion Channel Current by5MeODMT (in protein free perfusate) Concentration of 5MeODMT (µM) 1 3 1035 Mean ± SD % inhibition (n=3 cells) 5.03 ± 1.95% 23.77 ± 6.10% 52.72 ±2.61 % 82.22 ± 1.91%

The calculated IC₅₀ of 5MeODMT for hERG potassium channel current was8.69 µm (95% confidence limits 5.78-13.06 µm) compared to 12.8 nM (95%confidence limits 6.8-24.3 nM) for the positive control, terfenadine.

In Vivo Study

The pharmacological effects of BPL-5MEO on cardiovascular function(arterial blood pressure and ECG) was monitored by telemetry, inconscious male beagle dogs, following a single intranasaladministration.

The highest dose level was selected based on the results from anintranasal maximum tolerated dose (MTD) toxicity study in dogs (Study62958) where repeated daily dosing 2.5 mg/kg/day of BPL-MEO once dailyfor 5 consecutive days was marginally tolerable and associated withtransient clinical observations of moderate to severe incoordination,vocalization, salivation, shaking, circling, sneezing, decreasedactivity, and labored respiration that resolved within 60 minutes postdosing. Therefore, the highest dose selected for this study was 1.2mg/kg/day. The lowest dose of 0.4 mg/kg/day was based on considerationof a maximum clinical dose of 14 mg/day, with the mid-dose of 0.8mg/kg/day selected to provide a dose-response assessment.

BPL-5MEO and control/vehicle were administered by intranasalinstillation to both nostrils per session to a total of 4 dogs. Each dogreceived 4 administrations (control/vehicle and 3 dose levels ofBPL-5MEO) according to a Latin-square design, such that each dogreceived the various administrations in a unique sequence, as in Table10. A washout period of at least 2 days was allowed between eachsuccessive dose.

TABLE 10 Latin-square design for Dog Cardiovascular Study Test SessionTreatment 1001A 1002A 1003A 1004A^(a) 1104A 1 Control/Vehicle Low DoseMid Dose High Dose - 2 High Dose Control/Vehicle Low Dose Mid Dose - 3Mid Dose High Dose Control/Vehicle - Low Dose 4 Low Dose Mid Dose HighDose - Control/Vehicle a Animal 1004A was replaced prior to dosing forTest Session 3 with animal 1104A due to low implant battery.

Low Dose, Mid Dose, High Dose were 0.4, 0.8, and 1.2 mg/kg/day,respectively. The nominal dose levels refer to the freebase of 5MeODMTsalt form.

The dose volume administered to each animal was 7 µL/kg/nostril. Noanimal exceeded a dose volume of 100 µL/nostril.

The Control/Vehicle was 0.1% hydroxypropyl methyl cellulose (HPMC) inwater.

The telemetry signals for arterial blood pressure and pulse rate, ECGs(heart rate [HR], RR, PR, QT, and QTcV intervals and QRS complexduration), body temperature, and locomotor activity, were recordedcontinuously over the telemetry recording period of at least 1.5 hoursbefore the start of dosing and for at least 24 hours postdosing.Systolic, diastolic and mean arterial blood pressures and pulse ratewere obtained from transmitter catheter inserted into the femoralartery. ECGs were obtained from the biopotential leads, from thetelemetry transmitter, in a Lead II configuration.

During the study, all animals were also monitored for mortality andclinical signs. Body weights were recorded for general health statuscheck and for dose calculation purposes only.

There were no deaths and no BPL-5MEO-related clinical signs during thestudy.

The morphology of the P-QRS-T waveforms remained normal and no rhythm orconduction abnormalities were observed in the ECGs between control andtreated groups. There were minor differences in the % change of mean HRaveraged between approximately 0 and 150 minutes postdose between alldose levels and the control vehicle. While mean % increases in mean HRincreased by 3.7% in the control vehicle during this period, compared tobaseline, the observed increases with the low, mid and high dose levelsof BPL-5MEO were respectively 7.6%, 10.3%, and 17.2%. However, arterialblood pressure did not seem to show any appreciable differences thatwere sufficient to have any effect on HR. No other findings wereobserved. The observed increases in mean HR with all dose levels werenon-adverse, reversible and did not show a typical dose relationship.

In conclusion, the single intranasal instillation of BPL-5MEO to bothnostrils at doses of 0.4, 0.8, and 1.2 mg/kg/day was well tolerated anddid not result in any effects on the cardiovascular system of consciousmale Beagle dogs.

Example 12: Absorption and Pharmacokinetics

In a 14-day intranasal toxicology in male and female rats (ITR report700041), plasma concentrations of 5MeODMT increased as a function of thedose administered. Peak (C_(max)) concentrations were reached within 2to 5 minutes post dosing (T_(max)) with apparent t_(½) ranging from 6.8to 9.4 minutes. Values trended lower on Day 14 compared to Day 1. Therewas no apparent sex difference and no evidence of accumulation withrepeated dosing.

In a 14-day intranasal toxicology study in male and female dogs (ITRreport 62959), plasma concentration of 5MeODMT increased as a functionof the dose administered. Peak concentrations were reached within 3 to14 minutes (T_(max)), post dosing with apparent elimination half-livesranging from 19 to 95 minutes. The values were not markedly different onDay 1 and Day 14. There was no apparent sex difference and no evidenceof accumulation with repeated dosing.

The data shows that across the dose ranges studied in rats (5, 20, 75mg/kg), and dogs (0.4, 0.8, 1.5, and 2.5 mg/kg), exposure was generallyincreased dose-dependently, but not consistently in a dose-proportionalmanner as some increases were more or less than dose-proportionalbetween different doses. The results do not indicate a saturation ofMAOA-mediated metabolism at the doses studied in these species as seenpreviously in mice.

Example 13: Toxicology

The toxicology program completed with BPL-5MEO consisted of non-pivotalsingle/repeat dose intranasal studies to determine the MTD in order tohelp select the highest doses for the pivotal 14-day GLP intranasaltoxicology studies in male and female Sprague Dawley rats and Beagledogs. The intranasal route of administration was used as this is theclinical route of administration. The species selected were based uponinformation from the published literature, preliminary PK information,availability of historical control information from the testinglaboratory, and their standard use and acceptance as appropriatesurrogates for intranasal administration. The experimental design of thepivotal 14-day studies included an assessment of systemic exposures(toxicokinetics) and a 14-day recovery period to assess reversibility ofany adverse or delayed responses. The once daily dosing for 14consecutive days in the pivotal studies was intended to providesufficient systemic exposure to characterize the toxicity potential fora drug substance with a very short half-life.

1. Non-Pivotal Single/Repeat Dose and Tolerance Studies A. MaximumTolerated Dose Followed by 7-Day Repeat-Dose Toxicology in Rats (Study700040)

The objectives of this non-GLP study were to determine the maximumtolerated dose and the toxicity profile of BPL-5MEO following intranasalinstillation in the rat. The study consisted of 2 parts. The objectiveof the first part (Dose Escalation Phase), was to determine the MTD ofBPL-5MEO following a single intranasal administration to Sprague-Dawleyrats. The doses used in part 1 were 15, 30, 50, 65, and 75 mg/kg. Eachsubsequent dose was administered following at least 24 hours from thecommencement of the previous dose. There were 2 males and 2 females ineach dose group. The objective of the second part (Main Study Phase),was to determine the toxicity of BPL-5MEO at the MTD of 75 mg/kgfollowing once daily intranasal administration for 7 consecutive days toSprague-Dawley rats.

All the dose formulation samples collected and analyzed were between89.2% and 101.3% of nominal concentration, and as such met theacceptance criteria for accuracy (100 ±15% of their nominalconcentration). Analysis was performed using a non-GLP HPLC-UV assay.

All female groups received their targeted doses in both parts. However,as the maximum feasible loading dose was not to exceed 25 µL/naris,regardless of body weight, mean achieved doses for the males at the 30were still 99.3%, 90.0%, 88.2%, and 89.6%, respectively and wereconsidered to be acceptable.

During Phase I, assessments of mortality, clinical signs and bodyweights were performed. All animals were observed for 14 days afterdosing, following which they were euthanized on Day 15 and subjected toa gross necropsy examination. The necropsy consisted of an externalexamination, including reference to all clinically-recorded lesions, aswell as a detailed internal examination.

Single intranasal administration of 5MeODMT at the dose levels up to 75mg/kg was tolerated. There was no mortality and gross pathology findingsat any dose. Body weight gain was slightly suppressed females at 75mg/kg. A range of clinical signs were observed and includedincoordination, shallow or increased respiration, sneezing, salivation,decreased activity, piloerection, white pasty material around penis (formales), ptosis, laying on the cage floor, and sensitive to touch andshaking. The incidence and severity of these findings evolved as afunction of the administered dose and were transient, with most beingresolved within 1-hour post dose. Based on the clinical signs andmaximal feasible volume/dose, 75 mg/kg was judged to be the MTD, andthis dose was selected for Phase 2.

During Phase 2, assessments of mortality, clinical signs and bodyweights were performed. Following dosing, all animals were euthanizedand subjected to a necropsy examination on Day 8. The necropsy consistedof an external examination, including reference to allclinically-recorded lesions, as well as a detailed internal examination.Study plan specific tissues/organs were collected and retained, thentrimmed and preserved promptly once the animal was euthanized but thesewere not further examined microscopically.

Intranasal administration of 5MeODMT at 75 mg/kg for 7 consecutive dayswas tolerated. There were no mortalities. Body weight gain was slightlysuppressed for both sexes. Transient clinical signs similar to those ofthe Phase I included incoordination, mydriasis, increased or shallowrespiration, gasping, sneezing, salivation, pale in colour, decreasedactivity, lying on the cage floor, piloerection, white pasty materialaround penis (for males), erect penis (for males), cold to touch,partially or completely closed eyes, sensitive to touch and shaking.These signs were generally less pronounced in terms of severity andincidence during the last few dosing days of this phase, and wereresolved daily following dosing within 1-hour post administration.Macroscopic observations of note were limited to dark/pale area of thelungs in 2/10 animals; however, in the absence of histopathologicalexamination, a possible test item-relationship of these findings couldnot be excluded.

B. Maximum Tolerated Dose Followed by 7-Day Repeat-Dose Toxicology inDogs (Study 62958)

The objectives of this study were to determine the maximum tolerateddose and the toxicity of the test item, 5MeODMT (as the hydrochloridesalt), following intranasal instillation in the dogs. In support ofthese objectives, the study consisted of 2 individual phases.

The test item was administered once by intranasal instillation to onemale and female dog for up to 5 dose levels until the highest tolerabledose (MTD) was determined as described in Table 11.

TABLE 11 Doses Administered in the Dose Escalation Phase in Study 62958Dosing Day ^(a) Group Designation Total Dose Level ^(b) (mg/kg) DoseConcentration (mg/mL) Dose Volume (µL/kg) Number of Animals MalesFemales Day 1 Dose 1 2 100 10 Right Nostril + 10 Left Nostril 1 1 Day 7Dose 2 4 200 Day 10 Dose 3 5 ^(d) 250 Day 14 Dose 4 3 150 Day 17 Dose 53.5 175 a Each subsequent dose was administered following a washoutperiod of minimum 3 days between doses. b Dose levels refer to thefreebase of BPL-5MEO salt form. c Targeted dose concentrations werecalculated based on an estimated body weight of 10 kg. d These animalswere dosed at higher dose level of 5 mg/kg.

There were no BPL-5MEO-related effects on mortality or bodyweights.Slight decreases in food intake were observed following administrationfor the male on Days 1 (Dose 1) and 9 (Dose 2) and for the female onDays 4 (Dose 1) and 9 (Dose 2). A range of clinical signs were observedand included gnawing cage wire, dilated pupils, changes in respiration,incoordination, decreased activity, vocalization, salivation, erectpenis (for males) and shaking. After the last escalating dose at 3.5mg/kg/day, the male animal presented a convulsion shortly after dosingwhich lasted for 8 minutes. All clinical signs disappeared within anhour after the dosing except for decreased activity, dilated pupils andlying on the cage floor which were present on few occasions at 1-hourpost dose or a few minutes after. The MTD for the test item wasconsidered to be 2.5 mg/kg.

In the phase 2 (dose confirmation), BPL-5MEO was administered at the MTDto one male and female dog once daily by intranasal instillation for 5consecutive days and then twice daily on Days 6 and 7 (minimum 4 hoursapart). During Phase 2, assessments of mortality, clinical signs, bodyweights and food consumption were performed. A series of blood sampleswere collected on Days 1 and 7 for determination of plasmaconcentrations of 5MeODMT using an LC/MS/MS method. Following the lastdosing, all animals were euthanized and subjected to a necropsyexamination on Day 8. The necropsy consisted of an external examination;including reference to all clinically-recorded lesions, as well as adetailed internal examination. Study plan specific tissues/organs werecollected and preserved following necropsy but were not further examinedmicroscopically.

There were no test item-related effects on mortality or bodyweights.Slight decreases in food intake were observed for the male animal on Day7 and for the female animal on Days 5 and 7. A range of clinical signswere observed and included muscle stiffness, gnawing cage wire, dilatedpupils, changes in respiration, decreased activity, incoordination,vocalization, salivation, erect penis (for the male) and shaking. Allclinical signs disappeared within an hour after the dosing except fordecreased activity, dilated pupils, and lying on the cage floor whichwere present on few occasions at 1-hour post dose or a few minutesafter. All observations were considered transient.

Toxicokinetic assessments were performed on Days 1 and 7; the maximumBPL-5MEO plasma concentration (C_(max)) ranged from 541 to 803 ng/mL andwas reached (T_(max)) within 2 to 15 minutes post dose in both sexes.Dose normalized AUCs ranged from 2980 to 7320 min*kg*ng/mL/mg in bothsexes. After T_(max), BPL-5MEO plasma concentrations declined at anestimated t_(½) from 19.1 to 34 minutes in both sexes. There were no sexdifferences in any of the measured toxicokinetic parameters on eitheroccasion. Over the 7-day treatment period, BPL-5MEO did not accumulatewhen administered daily by intranasal instillation.

2. Pivotal Studies A. A 14-Day Repeat-Dose Intranasal Toxicity StudyFollowed by a 14-Day Recovery Period in Rats (Study 700041)

The objective of this GLP study was to determine the toxicity andtoxicokinetic (TK) profile of BPL-5MEO following intranasal instillationin Sprague Dawley rats for 14 consecutive days and to assess thepersistence, delayed onset, or reversibility of any changes following a14-day recovery period.

BPL-5MEO and control/vehicle were administered to groups of rats oncedaily by intranasal instillation for 14 consecutive days as described inTable 12.

TABLE 12 Doses Administered in 14-Day Repeat Dose Study in Rats GroupNo. Group Designation Total Dose Level ^(b) (mg/kg /day) Dose Conc.(mg/mL) Dose Volume ^(d) (µL/kg) Number of Animals Main RecoveryToxicokinetic Male Female Male Female Male Female 1 Vehicle Control a 00 75 Right Nostril + 75 Left Nostril 10 10 5 5 3 3 2 Low Dose 5 33.3 1010 - - 6 6 3 Mid Dose 20 133.3 10 10 - - 6 6 4 High Dose 75 500 10 10 55 6 6 a Vehicle control animals were administered 0.1% Hydroxypropylmethyl cellulose (HPMC) in water. b Nominal dose levels refer to thefreebase of 5MeODMT salt form. c The dose volume administered to eachanimal was 75 µL/kg/nostril. d Dose volume was not to exceed 25µL/nostril for all animals regardless of their bodyweight.

The animals were monitored for mortality, clinical signs, respiratorymeasurements, body weights, food consumption, and body temperature.Ophthalmoscopic examinations and respiratory function tests wereperformed on all animals at scheduled timepoints. Clinical pathologyassessments (hematology, coagulation, clinical chemistry, andurinalysis) were evaluated at termination. Blood samples were collectedfrom the jugular vein from the TK animals on Days 1 and 14, for up to 8hours after treatment for bioanalysis of 5MeODMT concentrations inplasma and the subsequent calculation of toxicokinetic parameters.Following dosing, the Main animals were euthanized and subjected to acomplete necropsy examination on Day 15. The Recovery animals wereobserved for an additional 14 days and then euthanized and subjected toa complete necropsy examination on Day 28. TK animals were euthanizedafter the last blood collection and discarded without furtherexamination. At terminal euthanasia, selected tissues/organs wereweighed, and microscopic evaluations of a standard set of tissuesincluding the nasal turbinates (4 sections) and brain (7 sections) wereperformed for all Main and Recovery study animals.

Following dosing, animals in the Main group were euthanized andsubjected to a necropsy examination on Day 15. The animals in theRecovery group were observed for 14 days and then euthanized andsubjected to a necropsy examination on Day 28. For toxicokinetics, aseries of 8 blood samples (approximately 0.5 mL each) were collectedfrom all rats in the Toxicokinetic group (3 rats/sex/timepoint) on Days1 and 14 of the treatment period at 2, 5, 10, 15 and 30 minutes, and1.0, 3.0 and 8 hours after treatment. For control rats (3 rats/sex) inthe Toxicokinetic group only 1 sample was collected at the 15 minutespost dosing timepoint on Days 1 and 14.

Toxicity was based on the following parameters monitored:mortality/morbidity, clinical observations, body weights/gains, foodconsumption, ophthalmoscopy, clinical pathology (hematology,coagulation, chemistry, and urinalysis), necropsy observations, selectedorgan weights, and microscopic examination of a complete set of standardtissues including 4 cross levels of the nasal cavity and 7 sections ofthe brain.

Results

All the samples met the acceptance criteria for accuracy (100 ± 10% oftheir nominal concentration).

All animals were dosed without any major incidents and no sneezing wasnoted. All groups received their targeted doses on Days 1 to 10. As themaximum feasible loading dose was not to exceed 25 µL/naris (due tolimited nasal surface area), once the bodyweights exceeded 333 g, maleanimals in all groups received slightly lower dose levels on Days 11 to14. This was considered to have no impact on the study data as thedifferences were negligible.

No mortality occurred over the course of this study.

The observed clinical signs were as follows:

Group 2 (Low Dose)

Both male and female animals exhibited incoordination, shaking,salivation, decreased activity, lying on cage floor and sensitive totouch. For one female animal on Day 3, increased respiration was alsoobserved.

Group 3 (Mid Dose)

Both male and female animals exhibited incoordination, shaking (ortremor), increased or shallow respiration, mydriasis, salivation,decreased activity, partially closed eyes, lying on cage floor andsensitive to touch. Male animals also exhibited erect penis.

Group 4 (High Dose)

Both male and female animals exhibited incoordination, shaking (ortremor), increased or shallow respiration, mydriasis, salivation,decreased activity, partially closed eyes, lying on cage floor andsensitive to touch. Male animals also exhibited erect penis.

Increased respiration was recorded for the mid and high dose group,however, measured respiratory values using plethysmographs proved thatthere were actually decreases in respiratory rates.

All the above clinical signs were considered to be transient for allgroups.

Slight, generally dose-dependent body weight gain suppression wasobserved for both sexes between Days 1 to 14. There were no changes infood consumption that could be attributed to treatment with at doselevels ≤75 mg/kg/day for 14 days.

On Day 14, slight body temperature increases were observed at 15 minutesand 30 minutes postdose for all treated male animals, for females on Day14, the body temperature increases were observed in one or all treatedgroups for all the timepoints (until 2 hours postdose). These increasesin body temperature were more pronounced in the mid (20 mg/kg/day) andhigh (75 mg/kg/day) dose groups.

When compared to pretreatment or control group, decreases in respiratoryrates were observed at 20 minutes postdose timepoint which resulted indecreases in respiratory minute volumes. Tidal volume values were eithercomparable to pre-dose or to control values. The 20-minute postdoserespiratory measurements on Day 1 was not performed for Group 2 femaleanimals inadvertently. This considered to have no impact on the studydata as the data could be extrapolated form the male animals in the samegroup. There were no significant between the sexes.

There was no adverse ocular effect, caused by the administration ofBPL-5MEO at dose levels ≤75 mg/kg/day for 14 days.

All other clinical observations, bodyweight changes, food consumptionchanges, and body temperature changes were considered to be notBPL-5MEO-related as they were sporadic, comparable to pretreatment signsor control animals, and not dose-related.

When compared to control Group, platelet, neutrophil, monocyte andbasophil counts were slightly increased in mid and high dose groups inboth sexes, however, these values were still within the historicalranges. On Day 28, all these values were compared to those in controlgroup.

All changes in the hematology parameters, including those that reachedstatistical significance, were not attributed to the administration ofBPL-5MEO as they were minor (within the normal physiological range),comparable to control values, and/or not dose-related.

When compared to control Group, activated partial thromboplastin times(APTT) were increased for both sexes in the mid (20 mg/kg/day) and high(75 mg/kg/day) dose groups. All the coagulation values on Day 28 werecomparable to control group. All other changes in the coagulationparameters were not attributed to the administration of BPL-5MEO as theywere minor (within the normal physiological range), comparable tocontrol values, and/or not dose-related.

There were no changes in clinical chemistry and urinalysis parametersthat could be attributed to the administration of BPL-5MEO at doselevels ≤75 mg/kg/day for 14 days. All changes in the parameters,including those clinical chemistry parameters that reached statisticalsignificance, were not attributed to the administration of BPL-5MEO asthey were minor (within the normal physiological range), comparable tocontrol values, and/or not dose-related.

Compared to control values, there were decreases in thymus weights(absolute and relative to terminal body weight) observed in male animalsas shown in Table 13.

TABLE 13 Thymus Weights for Male Animals Compared to Control Group Group(Males only) Thymus Mean Absolute Weight ^(a) Mean Relative to the BodyWeight ^(a) Control (Group 1) 0.6028 0.1756 Group 2 -4 -6 Group 3 18 -16Group 4 -31 -28 a For Control group, the organ weight in grams isreported, for other groups, the percentage compared to the control valueis shown.

All changes in the organ weight parameters, including those that reachedstatistical significance, were not attributed to the administration ofBPL-5MeO as they were minor, comparable to control values, and/or notdose related.

There were no macroscopic findings related to treatment with BPL-5MEO inrats in either the Main Recovery groups.

For animals in the Main group, microscopic findings related to treatmentwith BPL-5MEO, were noted in the nasal cavity sections 1, 2, 3 and 4 ofMain rats.

A range of minimal to mild changes were noted in the respiratory,transitional, and/or olfactory epithelium of the nasal cavities, 1, 2,3, and 4. The incidence and severity of changes were greater in malescompared to females and were proportional to the dose of BPL-5MEO.

Microscopic changes observed in rats dosed with 75 mg/kg/day of BPL-5MEO(Group 4) included: respiratory epithelium, minimal to milddegeneration, hyperplasia, and squamous metaplasia, minimal mononuclearinfiltrate and/or lumen exudate in nasal cavities 1, 2, 3, and/or 4;transitional epithelium, minimal hyperplasia in nasal cavity 1, and;olfactory epithelium, minimal to mild degeneration and/or minimalmononuclear infiltrate and erosion in nasal cavities 2, 3, and/or 4.Minimal degeneration of the olfactory epithelium of the nasal cavities 2and 3 was noted in male and/or female rats dosed with 5 and/or 20mg/kg/day of BPL-5MEO (Group 2 and 3). Minimal degeneration of therespiratory epithelium of the nasal cavities 1 and 2 was noted in maleand/or female rats dosed with 20 mg/kg/day of BPL-5MEO (Group 3).

For animals in the Recovery group, microscopic findings related totreatment with BPL-5MEO, were noted in the nasal cavity sections 1, 2,3, and 4 of Recovery rats. Minimal to mild changes were noted in therespiratory and olfactory epithelium of the nasal cavities, 1, 2, 3,and/or 4. The incidence and severity of changes were greater in malescompared to females. Microscopic changes included minimal to milddegeneration of respiratory epithelium in nasal cavities 1 and 2 andminimal degeneration olfactory epithelium in nasal cavities 2, 3, and 4indicating incomplete but progressive ongoing reversal of epithelialdegeneration following a 14-day recovery period. There was completereversal of all other microscopic changes noted previously in the nasalcavities of Main rats following a 14-day recovery period includingreversal of epithelial hyperplasia, squamous metaplasia, mononuclearinfiltrate, erosion, and lumen exudate.

Other microscopic findings in both the Main and Recovery groups wereconsidered to be procedure-related or incidental as they were notdose-related, of low incidence or severity, and/or as they were alsoseen in the control animals.

Toxicokinetics

Over the dose range, exposure to 5MeODMT (based on the area under theplasma drug concentration-time curve from the time of dosing to the lastquantifiable concentration [AUC_(0-Tlast) ] values) on Days 1 and 14generally increased dose-dependently (except for Group 4 as statedbelow), but not consistently in a dose-proportional manner as someincreases were more or less than dose-proportional between differentdoses. Furthermore, on Day 14, the exposure in Female group 4 (75mg/kg/day) decreased compared to Female Group 3 (20 mg/kg/day).

The sex ratios ranged between 0.4 and 6.2, but as the sex ratio randomlyvaried between dose groups and occasions, it was considered there was nosex-related difference.

Accumulation ratios (based on AUC_(0-Tlast)) ranged sporadically from0.3 to 2.9 (Day 14/Day1) suggesting that 5MeODMT does not accumulatewhen administered once daily for 14 consecutive days (2 weeks) byintranasal instillation in the Sprague Dawley rats at doses up to 75mg/kg/days.

The mean toxicokinetic parameters for Groups 2, 3, and 4 are presentedin Table 14.

TABLE 14 Mean Toxicokinetic Parameters From Study 700041 Group Dose(mg/kg/day) Parameter Day 1 Day 14 Male Female Male Female 2 5 T_(max)(h) 0.0833 0.166 0.0833 0.0333 AUC_(0-Tlast) [SE] (AUC_(INF_obs))(h*ng/mL) 39.9 [7.35] (40.1) 53.2 [15.9] (53.7) 114 [13.8] (115) 63.8[4.55] (64.0) C_(max) [SE] (ng/mL) 191 [45.6] 186 [98.7] 627 [102] 645[106] t_(½) (h) 0.137 0.150 0.142 0.113 3 20 T_(max) (h) 0.0333 0.08330.0333 0.0833 AUC_(0-Tlast) [SE] (AUC_(INF_obs)) (h*ng/mL) 420 [62.1](421) 198 [15.2] (198) 133 [57.002] (133) 169 [21.2] (169) C_(max) [SE](ng/mL) 4190 [1040] 679 [162] 1200 [857] 795 [115] t_(½) (h) 0.125 0.1400.143 0.147 4 75 T_(max) (h) 0.0333 0.0333 0.0333 0.0333 AUC_(0-Tlast)[SE] (AUC_(INF_obs)) (h*ng/mL) 1030 [114] (1040) 228 [49.7] (228) 391[228] (392) 155 [53.8] (156) C_(max) [SE] (ng/mL) 7010 [1010] 1310 [802]3290 [2510] 870 [361] t_(½) (h) 0.133 0.156 0.116 0.130 Abbreviations:AUC_(0-Tlast) = Area under the plasma drug concentration-time curve fromthe time of dosing to the last quantifiable concentration; AUC_(INF_obs)= Area under the plasma drug concentration-time curve from the time ofdosing extrapolated to infinity; C_(max) = The maximum plasmaconcentration; h = hours; SE = standard error of mean; t_(½) = Terminalelimination half-life; T_(max) = Time to maximum plasma concentration.

Conclusion

Intranasal administration of BPL-5MEO at dose levels ≤75 mg/kg/day for14 consecutive days was tolerated with no BPL-5MEO-related effects onmortality, ophthalmology, clinical chemistry, macroscopic findings andurinalysis. Slight dose-dependent body weight gain suppression wasobserved for both sexes. Transient clinical signs includedincoordination, shaking (or tremor), increased or shallow respiration,mydriasis, salivation, decreased activity, partially closed eyes, lyingon cage floor and sensitive to touch. Male animals also exhibited erectpenis. Slight dose dependent body temperature increases were observedfor both sexes.

Decreases in respiratory rates were observed at 20 minutes post dosetimepoint which resulted in decreases in respiratory minute volumes.Platelet, neutrophil, monocyte and basophil counts were slightlyincreased in mid and high dose groups in both sexes. APTT were increasedfor both sexes for main animals in the mid (20 mg/kg/day) and high (75mg/kg/day) dose groups. There were decreases in thymus weights (absoluteand relative to terminal bodyweight) observed in male animals.Microscopic changes were noted in nasal cavities 1, 2, 3, and/or 4involving the respiratory, olfactory, and transitional epithelium. Theincidence and severity of findings were greater in males compared tofemales and were proportional to the dose of BPL-5MEO with incompletebut progressive on-going reversal following a 14-day recovery period.

The NOAEL was reported as the lowest dose of 5 mg/kg.

B. A 14-Day Repeat-Dose Intranasal Toxicity Study Followed by a 14-DayRecovery Period in Dogs (Study 62959)

The objective of this GLP study (Study 62959) was to determine thetoxicity and TK profile of BPL-5MEO following intranasal instillation inBeagle dogs for 14 consecutive days and to assess the persistence,delayed onset, or reversibility of any changes following a 14-dayrecovery period.

BPL-5MEO and control/vehicle were administered to groups of dogs oncedaily by intranasal instillation for 14 consecutive days as described inTable 15.

TABLE 15 Doses Administered in 14-Day Repeat Dose Study in Dogs GroupNumber Group Designation Total Dose Level ^(b) (mg/kg/day) Dose Conc.(mg/mL) Dose Volume ^(d,) ^(e) (µL/kg) Number of Animals Main RecoveryMale Female Male Female 1 Vehicle Control ^(a) 0 0 10 Right Nostril + 10Left Nostril 3 3 2 2 2 Low Dose 0.4 20 3 3 - - 3 Mid Dose 0.8 40 3 3 - -4 High Dose 2.5 & 1.5^(c) 125 & 75^(c) 3 3 2 2 a Vehicle control animalswere administered 0.1% Hydroxypropyl methyl cellulose (HPMC) in water. bDose levels refer to the freebase of 5MeODMT salt form. c Replicate Ahigh dose animals showed severe clinical signs of muscle stiffness(rigidity), tachycardia, tachypnea, hyperthermia and aggressivenessafter dosing on Day 1 at the dose level of 2.5 mg/kg. The dose level wassubsequently decreased on Day 1 for the Replicates B and C to 1.5 mg/kg.Replicate A received 1.5 mg/kg on Days 2 to 14. d The dose volumeadministered to each animal was 10 µL/kg/nostril. e Dose volume was notto exceed 100 µL/nostril for all animals regardless of their bodyweight.

Assessments of mortality, clinical signs, olfactory reflex, bodyweights, food consumption, ophthalmology, and electrocardiograms wereperformed. In addition, clinical pathology assessments (hematology,coagulation, clinical chemistry and urinalysis) were evaluated oncepretreatment and at termination. Blood samples were collected from thejugular vein of all animals on Days 1 and 14, at up to 8 time pointsrelative to treatment, for analysis of test item concentration in plasmaand the subsequent calculation of toxicokinetic parameters. Followingdosing, the Main animals were euthanized and subjected to a completenecropsy examination on Day 15. The Recovery animals were observed foran additional 14 days test article free and then euthanized andsubjected to a complete necropsy examination on Day 28. All Main andRecovery study animals underwent complete necropsy examinations,selected tissues/organs were retained, and microscopic evaluations of astandard set of tissues were performed.

For toxicokinetics, a series of 8 blood samples were collected from thejugular vein from all treated animals on each of Days 1 and 14 of thetreatment period at 2, 5, 10, 15, 30, and 60 minutes as well as 3 and 8hours after treatment. For Group 1, only one sample was taken at 15minutes post dosing on Days 1 and 14 in order to confirm the absence ofBPL-5MEO in animals in the vehicle control group. Blood samples wereanalysed for the BPL-5MEO concentration in plasma and the subsequentcalculation of TK parameters.

Results

All the dose formulation samples collected and analyzed met theacceptance criteria for accuracy (100 ± 10% of their nominalconcentration).

Daily intranasal administration of BPL-5MEO to both nostrils of Beagledogs once daily for 14 consecutive days at dose levels up to 1.5mg/kg/day did not cause any mortality. High dose animals initially givento a subset of dogs at 2.5 mg/kg and showed severe clinical signs ofmuscle stiffness (rigidity), tachycardia, tachypnea, hyperthermia andaggressiveness after dosing on Day 1 and this dose exceeded the MTD. Thehigh dose was subsequently lowered on Day 2 to 1.5 mg/kg/day and thisdose was tolerated. Animals in all treated Groups exhibited transientclinical observation of incoordination, vocalization, mydriasis,decreased or increased activity, increased respiration, gnawing cagewire, excessive licking of nose or lips and circling. In addition, eyedischarge and shaking were observed in the Mid and High dose groups.Erect penis was also recorded for the high dose male animals. All theseclinical signs were considered to be exacerbated pharmacologymanifestations, occurred within 10 to 30 minutes of dosing, and wereresolved within 90 minutes.

When compared to control Group, the triglyceride level of ⅓ Group 3female, ⅕ Group 4 male and ⅘ Group 4 females were increased, these dataare presented in Table 16. There were no other treatment-relatedclinical pathology findings.

TABLE 16 Mean ± SD Day 14 Triglyceride Values Compared to Control GroupGroup Dose (mg/kg/day) Triglyceride (mmol/L) Males ^(a) Females ^(a)Group 1 Control 0.38 ± 0.13 0.34 ± 0.12 Group 2 0.4 0.40 ± 0.11 0.46 ±0.61 Group 3 0.8 0.44 ± 0.07 0.47 ±0.22 Group 4 2.5 & 1.5^(b) 0.42 ±0.16 0.69 ± 0.24 Abbreviations: SD = standard deviation

-   a′ for Control group, the control value is mentioned, for other    groups, the percentage compared to the control value is shown.-   b Replicate A high dose animals showed severe clinical signs of    muscle stiffness (rigidity), tachycardia, tachypnea, hyperthermia    and aggressiveness after dosing on Day 1 at the dose level of 2.5    mg/kg. The dose level was subsequently decreased on Day 1 for the    Replicates B and C to 1.5 mg/kg. Replicate A received 1.5 mg/kg on    Days 2 to 14.

All other changes in the clinical chemistry parameters, including thosethat reached statistical significance, were not attributed to theadministration of BPL-5MEO as they were minor (within the normalphysiological range), comparable to control values, and/or not doserelated.

There were no changes in olfactory reflex, food consumption, bodyweight, ocular effect, or ECG that could be clearly attributed totreatment with BPL-5MEO at a dose level ≤1.5 mg/kg/day for 14 days. Allbody weight changes were not attributed to the administration of thetest item as they were minor, and not toxicologically relevant. All foodconsumption changes, including those that were statisticallysignificant, were not attributed to the administration of the test itemas they were minor, and not toxicologically relevant.

Animals showed hyperthermia at the dose level of 2.5 mg/kg/day on Day 1.Transient body temperature increases were observed on Day 14 for highdose group in both sexes at 15 and 30 minutes postdose. All other bodytemperature changes were not attributed to the administration of thetest item as they were minor, and not toxicologically relevant.

Histopathological examination results for Main animals included minimalto moderate decreased cellularity of the thymic lymphocytes at doselevels of 0.8 (1 male) and 1.5 mg/kg/day (3 males), which was determinedas stress related. Minimal epithelial metaplasia of respiratoryepithelium in the nasal cavities found at dose levels of 0.8 (1 female)and 1.5 mg/kg/day (2 males) and minimal to mild mononuclear cellinfiltrate of the olfactory epithelium in the nasal cavities seen at adose level of 1.5 mg/kg/day (1 male/1 female) were considered to besigns of irritation caused by BPL-5MEO but not adverse.

In animals euthanized after a 14-day recovery period, only minimalmononuclear cell infiltrate of the olfactory epithelium in the nasalcavities was still present at a dose level of 1.5 mg/kg/day (1 female)but at a lower severity when compared with animals euthanizedterminally, indicative of recovery. Decreased cellularity of thymiclymphocytes was no longer observed.

Toxicokinetics

BPL-5MEO was not detected in any of the samples collected from theControl (Group 1) animals on Days 1 and 14.

The mean toxicokinetic parameters for Groups 2, 3, and 4 are presentedin the table below.

Mean Toxicokinetic Parameters From Study 62959 Group Dose (mg/kg/day)Parameter Day 1 Day 14 Male Female Male Female 2 0.4 T_(max) (h) 0.09420.194 0.111 0.0942 AUC_(0-Tlast) (AUC_(INF_) _(obs)) (h*ng/mL) 77.9(80.9) 104 (106) 70.6 (77.7) 86.4 (95.9) C_(max) ₍ng/mL) 343 242 285 196t_(½) (h) 0.571 0.312 0.429 0.706 3 0.8 T_(max) (h) 0.111 0.139 0.1110.0833 AUC_(0-Tlast) (AUC_(INF_) _(obs)) (h*ng/mL) 152 (160) 261 (265)298 (322) 248 (279) C_(max) (ng/mL) 300 328 411 244 t_(½) (h) 0.5950.730 1.32 1.59 4 2.5 & 1.5^(a) T_(max) (h) 0.146 0.111 0.223 0.0898AUC_(0-Tlast) (AUC_(INF_) _(obs)) (h*ng/mL) 277 (280) 263 (271) 260(287) 165 (167) C_(max) (ng/mL) 561 348 464 379 t_(½) (h) 0.718 0.8480.816 0.725 Abbreviations: AUC_(0-Tlast) = Area under the plasma drugconcentration-time curve from the time of dosing to the lastquantifiable concentration; AUC_(INF_obs) = Area under the plasma drugconcentration-time curve from the time of dosing extrapolated toinfinity; C_(max) = The maximum plasma concentration; h = hours; t_(½) =Terminal elimination half-life; T_(max) = Time to maximum plasmaconcentration. a Replicate A high dose animals showed severe clinicalsigns of muscle stiffness (rigidity), tachycardia, tachypnea,hyperthermia and aggressiveness after dosing on Day 1 at the dose levelof 2.5 mg/kg. The dose level was subsequently decreased on Day 1 for theReplicates B and C to 1.5 mg/kg. Replicate A received 1.5 mg/kg on Days2 to 14.

Over the dose range, exposure to BPL-5MEO (based on AUC_(0-Tlast)values) on Days 1 and 14 generally increased dose-dependently (exceptfor Group 4 as stated below), but not consistently in adose-proportional manner as some increases were more or less thandose-proportional between different doses. Furthermore, on Day 14, theexposure in Group 4 (1.5 mg/kg/day) decreased compared to Group 3 (0.8mg/kg/day).

There were no marked sex-related differences in any of the measuredtoxicokinetic parameters, except on Day 14 where T_(max) occurredslightly later in Group 4 males as compared to Group 4 females. The sexratios (male/female), with the exception of Group 4 T_(max), rangedsporadically from 0.5 to 1.7 on Days 1 and 14.

Accumulation ratios (based on AUC_(0-Tlast)) ranged sporadically from0.6 to 2.0 (Day 14/Day1) suggesting that BPL-5MEO does not accumulatewhen administered once daily for 14 consecutive days (2 weeks) byintranasal instillation in beagle dogs at doses up to 1.5 mg/kg/day.

Conclusion

Based on the parameters examined where all the changes noted wereconsidered either non-adverse or related to exaggerated pharmacologicaleffects, the reported NOAEL for BPL-5MEO, when dosed for 14 consecutivedays by intranasal administration, followed by a 14-day recovery periodwas considered to be 1.5 mg/kg/day, corresponding to a C_(max) of 421ng/mL, and AUC_(0-Tlast) (AUC_(INF) _(_obs)) of 213 (220) h*ng/mL(combined for both sexes).

Toxicokinetic Considerations

Based on preliminary data from another ongoing study in dogs, it hasbeen observed that the site of blood sampling in dogs may impact themeasured plasma exposure. Samples from the jugular vein may result inhigher apparent exposure levels than samples from the cephalic vein,which might be due to the local transmucosal route of administration(also reported in the scientific literature (Illum, 2003; Sohlberg,2013)). Therefore, dose escalation criteria for the Phase 1 SingleAscending Dose study are based on assessment of clinical criteria,safety factors and exposure. A maximum dose of 14 mg has beendesignated. The Table below summarizes the clinical observations in therat and dog toxicity studies performed with BPL-5MEO. These clinicalsigns are considered to be related to the pharmacological activity ofBPL-5MEO and demonstrate a dose-related increase in severity of findingson both species, generally ranging from mild to moderate at 0.4 to 1.5mg/kg in dogs and 1.5 to 5 mg/kg in rats.

Summary of Clinical Observations in Applicant-Sponsored Animal Studies

Dog (HED) 0.4 mg/kg (14 mg) 0.8 mg/kg (26 mg) 1.5 mg/kg^(a) (50 mg) 2.5mg/kg (83 mg) 3.0 – 5.0 mg/kg (100 – 166 mg) Salivation MydriasisIncoordination Vocalization Decreased activity Increased activityIncreased respiration Gnawing cage wire Excessive licking CirclingMydriasis Salivation Excessive licking Incoordination VocalizationDecreased activity Increased activity Increased respiration Gnawing cagewire Circling Eye discharge Shaking Head shaking Slight tremor (1.0mg/kg) ^(b) Mydriasis Salivation, Excessive licking Dilated pupilVocalizing Tachypnea Increased respiration Tachycardia Muscle rigidityErect penis Twitches Tense abdomen Splay posture Lying on cage floorUncoordinated Circling Head shaking Tremor Myoclonic jerk ^(b)Salivation Pupil dilated Circling Muscle stiffness Activity decreasedIncreased respiration Diarrhea Hunched Erect penis Excessive groomingExcessive fear Hypersensitive to stimuli Aggressiveness Tachycardia Lossof righting reflex Hyperthermia (single dose) Shaking Tremors MydriasisSalivation Excessive licking Dilated pupil Vocalizing Laboredrespiration Gnawing cage Tongue outside Hunched Erect penis TremorShaking Lying Decreased activity Uncoordinated Aggressiveness CirclingNot responsive to stimuli Hyperthermia Convulsion Rat (HED) 1.5 mg/kg(14 mg) 3.0 mg/kg (29 mg) 5.0 mg/kg^(a) (48 mg) 10 mg/kg (96 mg) 20 - 75mg/kg (194 - 726 mg) Salivation Piloerection Increased respirationDilated pupils Decreased activity Decreased rearing Lying Hypothermia(single dose) Salivation Piloerection Increased respiration GaspingDilated pupils Decreased activity Decreased rearing Lying Hypothermia(single dose) Uncoordinated Tremor Salivation Piloerection Increasedrespiration Dilated pupils Slight hyperthermia (repeated dose)Uncoordinated Shaking Decreased activity Lying Sensitive to touchSalivation Piloerection Decreased activity Increased or shallowrespiration Gasping Lying Decreased rearing Hypothermia (single dose)Twitching Tremor Increased respiration Shallow respiration MydriasisSalivation Decreased activity Partially closed eyes Lying on cage floorSensitive to touch Erect penis Hyperthermia Uncoordinated Shaking (ortremor) Abbreviations: HED = Human Equivalent Dose (for a 60 kg human) a= NOAEL determined in the 14-day toxicology studies for both species. b= Preliminary data, ongoing study (Slight tremor was observed at 1.0mg/kg = 33 mg HED) Note: these signs were of short duration, andgenerally resolved within one to two hours in both species.

Example 14: Genotoxicity

The genotoxicity potential of 5MeODMT was evaluated in silico(computational analysis) for structural alerts and in vitro in GLPassays to assess mutagenic and clastogenic potential following the ICHS2 (R1) Guidance.

In Silico

5MeODMT, its primary active metabolite, bufotenine, and an identifieddrug substance impurity, MW234, were evaluated for quantitativestructural activity relationships for potential mutagenicity and/orcarcinogenicity using two computation analytical methods, Derek Nexusand the Leadscope Genetox Statistical Models. The evaluation from bothanalyses did not identify any structural alerts associated with 5MeODMTor bufotenine, and a possible nor an identified drug substance impurityMW234.

In Vitro Mutagenicity

The mutagenic potential of 5MeODMT was evaluated in a GLP BacterialReverse Mutation Test (Ames test) for the ability to induce reversemutations at selected loci of Salmonella typhimurium tester strainsTA98, TA100, TA1535, and TA1537 and the Escherichia coli tester strainWP2uvrA. These strains were treated with 5MeODMT at concentrations of1.6, 5, 16, 50, 160, 500, 1600 and 5000 µg per plate along with thevehicle/negative and appropriate positive controls. The assay wasperformed in triplicate using the pre-incubation method in the absenceand presence of an exogenous metabolic activation system,phenobarbital/5,6-benzoflavone-induced rat liver S9 microsomal enzymemix (S9 mix)

A slight cytotoxicity was seen at the concentration of 1600 µg/plate inall S. typhimurium strains. Although higher levels of cytotoxicity wereobserved at 5000 µg/plate in the absence of S9 mix, it remained slightin the presence of S9 mix in these strains. No cytotoxicity was noted inthe E. coli strain in either the absence or presence of S9 mix.

Overall, no increases (≥2× of the vehicle/negative values) in the numberof revertant colonies per plate was observed with 5MeODMT in S.typhimurium tester strains TA1535, TA100, E. coli WP2uvrA in either theabsence and presence of S9 or with TA1537 and TA98 in the presence of S9mix. Three exceptions were a 2.1-fold increase at 1600 µg/plate withoutS9 seen in E. coli WP2uvrA, a 2.0-fold increase in S. typhimurium TA1537at 50 µg/plate with S9, and 2.1-fold increase in S. typhimurium TA1535at1600 µg/plate with S9. However, these values were not consideredbiologically relevant as the values were within laboratory’s historicalvehicle/negative control range and were not dose-related.

Two of the 5MeODMT-treated S. typhimurium strains, TA1537 and TA98, inthe absence of S9 mix, showed a number of revertant colony countsslightly higher than twice of the vehicle/negative values at 160µg/plate and 500 µg/plate with fold-increases at 2.3- and 2.7-fold inTA1537 and 2.2- and 2.4-fold in TA98. The increased colony countsobserved in these strains were still within the laboratory’s historicalvehicle/negative control range and were not overall dose-related;therefore, they did not meet the criteria of positive results. However,as the increases were seen in TA98 and TA1537 in 2 adjacent dose levelsand that 2 strains showed a similar trend of increases in revertantcolony counts at the same concentration levels, the results were judgedequivocal. Therefore, the bacterial reverse mutation test was repeatedin the absence of S9 mix for these 2 strains in order to investigatethese equivocal results. The repeat test used a narrower concentrationrange of 15, 30, 60, 120, 250, 500, 1000, and 2000 µg per plate. Theresults from repeated test showed no increases in the revertant coloniesnumber per plate for both 5MeODMT-treated strains in all concentrationlevels tested up to the maximal dose of 2000 µg/plate. Therefore, it wasconcluded that the small increases observed in the first test for S.typhimurium tester stains TA 1537 and TA98 were not biologicallyrelevant.

In conclusion, the results of the bacterial reverse mutation assaysindicated that 5MeODMT did not induce any increase in revertant colonynumbers with any of the bacteria strains tested either in the absence orpresence of the rat liver S9 microsomal metabolic activation system.5MeODMT has no mutagenic potential in the bacterial reverse mutationtest. The expected response of the positive and negative controlsaffirmed the sensitivity and validity of assay.

In Vitro Clastogenicity

The clastogenic potential of 5MeODMT was evaluated in a GLP in vitromicronucleus test using Chinese hamster ovary (CHO)-K1 cells using flowcytometry. Exponentially growing cells were treated in duplicate withthe 5MeODMT at 9 concentrations up to the recommended upper limit of 1mM (corresponding to approximately 300 µg/mL): 1.25, 2.5, 5.0, 10, 20,40, 80, 150 and 300 µg/mL. The treatment with the vehicle/negative andpositive controls was concurrently performed. There were 3 treatmentregimens: a 4-hour-short exposure in either absence or presence of anexogenous metabolic activation system, phenobarbital/5,6 benzoflavonerat liver S9 microsomal enzyme mix (S9 mix), and a 26 hour-extendedexposure, considered a confirmatory phase, in the absence of S9 mix.

No cytotoxicity or precipitation was observed in 5MeODMT-treated cellsup to the maximal dose level of 300 µg/mL throughout the treatmentperiods. In all treatment regimens, the results of the in vitromicronucleus test indicate that 5MeODMT did not induce any increases inmicronuclei or hypodiploid cells either in the absence or presence ofthe rat liver S9 microsomal metabolic activation system. In conclusion,5MeODMT showed no chromosome-damaging potential in the in vitromicronucleus test with CHO-K1 cells. The expected response of thepositive and negative controls affirmed the sensitivity and validity ofassay.

Reproductive and Development Toxicity

Reproductive and developmental toxicity studies have not been conducted.In the 14-day pivotal GLP intranasal toxicity studies in rats and dogs,there was no evidence of an adverse effect on reproductive tissues withsystemic exposure to BPL-5MEO.

Example 15: Formulation

BPL-5MEO has been synthesised to Good Manufacturing Practice (GMP)standards and prefilled into the Aptar Unidose Intranasal LiquidDelivery System device. The device allows a single fixed dose ofBPL-5MEO to be administered intranasally. The liquid is prefilled intoand administered using a standard single unit dose nasal pump device.Excipients used in the formulation are water, 0.1% hydroxypropylmethylcellulose (HPMC) and sodium hydroxide (NaOH). Two concentrationsof the formulation will be used, 70 mg/mL (for dose levels below 7 mg),and 140 mg/mL (for dose levels above 7 mg).

In an embodiment, there is provided a composition comprising 5MeODMThydrochloride, wherein the composition comprises:

-   water;-   0.1% hydroxypropyl methylcellulose (HPMC);-   0.1% sodium hydroxide (NaOH); and-   70 mg/ml 5MeODMT.

In an embodiment, there is provided a composition comprising 5MeODMTbenzoate, wherein the composition comprises:

-   water;-   0.1% hydroxypropyl methylcellulose (HPMC);-   0.1% sodium hydroxide (NaOH); and-   70 mg/ml 5MeODMT.

In an embodiment, there is provided a composition comprising 5MeODMThydrochloride, wherein the composition comprises:

-   water;-   0.1% hydroxypropyl methylcellulose (HPMC);-   0.1% sodium hydroxide (NaOH); and-   140 mg/ml 5MeODMT.

In an embodiment, there is provided a composition comprising 5MeODMTbenzoate, wherein the composition comprises:

-   water;-   0.1% hydroxypropyl methylcellulose (HPMC);-   0.1% sodium hydroxide (NaOH); and-   140 mg/ml 5MeODMT.

In an embodiment, there is provided an intranasal composition comprising5MeODMT hydrochloride, wherein the composition comprises:

-   water;-   0.1% hydroxypropyl methylcellulose (HPMC);-   0.1% sodium hydroxide (NaOH); and-   70 mg/ml 5MeODMT.

In an embodiment, there is provided an intranasal composition comprising5MeODMT benzoate, wherein the composition comprises:

-   water;-   0.1% hydroxypropyl methylcellulose (HPMC);-   0.1% sodium hydroxide (NaOH); and-   70 mg/ml 5MeODMT.

In an embodiment, there is provided an intranasal composition comprising5MeODMT hydrochloride, wherein the composition comprises:

-   water;-   0.1% hydroxypropyl methylcellulose (HPMC);-   0.1% sodium hydroxide (NaOH); and-   140 mg/ml 5MeODMT.-   In an embodiment, there is provided an intranasal composition    comprising 5MeODMT benzoate, wherein the water;-   0.1% hydroxypropyl methylcellulose (HPMC);-   0.1% sodium hydroxide (NaOH); and-   140 mg/ml 5MeODMT.

composition comprises:

In an embodiment, the composition comprises 25-400 mg/mL; 25-300 mg/mL;25-200 mg/mL; 25-100 mg/mL; 25-50 mg/mL; 50-400 mg/mL; 50-300 mg/mL;60-400 mg/mL; 60-300 mg/mL; 150-400 mg/mL; 150-300 mg/mL; 200-300 mg/mL;200-400 mg/mL; 30-100 mg/mL; 300-400 mg/mL; 300-500 mg/mL; 45-75 mg/mL;50-70 mg/mL; 55-65 mg/mL; or 50-60 mg/mL 5MeODMT.

In an embodiment, there is provided an intranasal liquid delivery systemcomprising a composition of 5MeODMT.

In an embodiment, there is provided a single unit dose capsule of acomposition of 5MeODMT.

In an embodiment, there is provided an intranasal composition comprisinga dosage amount 50-150 mg/ml 5MeODMT in a liquid medium, wherein the5MeODMT is formulated as the benzoate salt of 5MeODMT (5MeODMTbenzoate).

In an embodiment, 5MeODMT benzoate is present as a suspension oremulsion in the liquid medium.

In an embodiment, there is provided an intranasal liquid delivery systemcomprising:

-   70 to 140 mg/ml of 5MeODMT benzoate as a suspension or emulsion in a    liquid medium.

Example 16: Administration

BPL-5MEO is administered to subjects by a trained member of the researchteam using a single unit dose pump spray. The unit contains only 1spray, so should not be tested before use. While sitting down thesubject is asked to blow their nose to clear the nasal passages. Oncethe tip of the device is placed into the nostril the clinic staff willpress the plunger to release the dose.

In an embodiment, there is provided a method for the administration of5MeODMT comprising administering the 5MeODMT as an instranasal spray toa human subject wherein the human subject has followed patientpreparation parameters that include blowing their nose to clear theirnasal passages immediately prior to administration.

In an embodiment, the human subject is seated.

In an embodiment, there is provided a method for the delivery of 5MeODMTto the brain of a human subject comprising administering the 5MeODMT asan instranasal spray to a human subject wherein the human subject hasfollowed patient preparation parameters that include blowing their noseto clear their nasal passages immediately prior to administration.

Example 17: X-Ray Powder Diffraction (XRPD) of 5MeODMT Benzoate

The XRPD pattern of 5MeODMT benzoate salt, was acquired before andfollowing particle size reduction with a mortar and pestle. This reducedthe intensity of dominant diffractions and revealed that the XRPDpattern of the benzoate salt was prone to preferred orientation prior toparticle size reduction, which is a function of the habit and particlesize of the material. XRPD patterns of the benzoate salt prior to andfollowing particle size reduction can be seen in FIGS. 6 and 7respectively. The XRPD patterns of the benzoate salt prior to andfollowing particle size reduction overlaid on one another can be seen inFIG. 8 .

In an embodiment, there is provided crystalline 5MeODMT benzoate,characterised by peaks in an XRPD diffractogram at 17.5, 17.7 and21.0°2θ±0.1°2θ.

In an embodiment, there is provided crystalline 5MeODMT benzoate,characterised by peaks in an XRPD diffractogram at 17.5, 17.7 and21.0°2θ±0.2°2θ.

In an embodiment, there is provided crystalline 5MeODMT benzoate,characterised by peaks in an XRPD diffractogram at 17.5, 17.7 and21.0°2θ±0.3°2θ.

In an embodiment, there is provided crystalline 5MeODMT benzoate,characterised by peaks in an XRPD diffractogram at 17.5, 17.7 and21.0°2θ±0.1°2θ as measured by x-ray powder diffraction using an x-raywavelength of 1.5406 Å.

In an embodiment, there is provided crystalline 5MeODMT benzoate,characterised by peaks in an XRPD diffractogram at 17.5, 17.7 and21.0°2θ±0.2°2θ as measured by x-ray powder diffraction using an x-raywavelength of 1.5406 Å.

In an embodiment, there is provided crystalline 5MeODMT benzoate,characterised by peaks in an XRPD diffractogram at 17.5, 17.7 and21.0°2θ±0.3°2θ as measured by x-ray powder diffraction using an x-raywavelength of 1.5406 Å.

In an embodiment, there is provided crystalline 5MeODMT benzoate,characterised by peaks in an XRPD diffractogram at 17.5, 17.7, 21.0 and25.3°2θ±0.1°2θ.

In an embodiment, there is provided crystalline 5MeODMT benzoate,characterised by peaks in an XRPD diffractogram at 17.5, 17.7, 21.0 and25.3°2θ±0.2°2θ.

In an embodiment, there is provided crystalline 5MeODMT benzoate,characterised by peaks in an XRPD diffractogram at 17.5, 17.7, 21.0 and25.3°2θ±0.3°2θ.

In an embodiment, there is provided crystalline 5MeODMT benzoate,characterised by peaks in an XRPD diffractogram at 17.5, 17.7, 21.0 and25.3°2θ±0.1°2θ as measured by x-ray powder diffraction using an x-raywavelength of 1.5406 Å.

In an embodiment, there is provided crystalline 5MeODMT benzoate,characterised by peaks in an XRPD diffractogram at 17.5, 17.7, 21.0 and25.3°2θ±0.2°2θ as measured by x-ray powder diffraction using an x-raywavelength of 1.5406 Å.

In an embodiment, there is provided crystalline 5MeODMT benzoate,characterised by peaks in an XRPD diffractogram at 17.5, 17.7, 21.0 and25.3°2θ±0.3°2θ as measured by x-ray powder diffraction using an x-raywavelength of 1.5406 Å.

In an embodiment, there is provided crystalline 5MeODMT benzoate,characterised by peaks in an XRPD diffractogram at 9.0, 11.5, 14.5,16.5, 17.5, 17.7, 18.5, 21.0, 22.7, 24.7 and 25.3°2θ±0.1°2θ.

In an embodiment, there is provided crystalline 5MeODMT benzoate,characterised by peaks in an XRPD diffractogram at 9.0, 11.5, 14.5,16.5, 17.5, 17.7, 18.5, 21.0, 22.7, 24.7 and 25.3°2θ±0.2°2θ.

In an embodiment, there is provided crystalline 5MeODMT benzoate,characterised by peaks in an XRPD diffractogram at 9.0, 11.5, 14.5,16.5, 17.5, 17.7, 18.5, 21.0, 22.7, 24.7 and 25.3°2θ±0.3°2θ.

In an embodiment, there is provided crystalline 5MeODMT benzoate,characterised by peaks in an XRPD diffractogram at 9.0, 11.5, 14.5,16.5, 17.5, 17.7, 18.5, 21.0, 22.7, 24.7 and 25.3°2θ±0.1°2θ as measuredby x-ray powder diffraction using an x-ray wavelength of 1.5406 Å.

In an embodiment, there is provided crystalline 5MeODMT benzoate,characterised by peaks in an XRPD diffractogram at 9.0, 11.5, 14.5,16.5, 17.5, 17.7, 18.5, 21.0, 22.7, 24.7 and 25.3°2θ±0.2°2θ as measuredby x-ray powder diffraction using an x-ray wavelength of 1.5406 Å.

In an embodiment, there is provided crystalline 5MeODMT benzoate,characterised by peaks in an XRPD diffractogram at 9.0, 11.5, 14.5,16.5, 17.5, 17.7, 18.5, 21.0, 22.7, 24.7 and 25.3°2θ±0.3°2θ as measuredby x-ray powder diffraction using an x-ray wavelength of 1.5406 Å.

In an embodiment, there is provided crystalline 5MeODMT benzoate,characterised by peaks in an XRPD diffractogram at 9.0, 11.5, 14.5,16.3, 16.5, 17.5, 17.7, 18.5, 21.0, 22.7, 24.7, 25.3 and 30.5°2θ±0.1°2θ.

In an embodiment, there is provided crystalline 5MeODMT benzoate,characterised by peaks in an XRPD diffractogram at 9.0, 11.5, 14.5,16.3, 16.5, 17.5, 17.7, 18.5, 21.0, 22.7, 24.7, 25.3 and 30.5°2θ±0.2°2θ.

In an embodiment, there is provided crystalline 5MeODMT benzoate,characterised by peaks in an XRPD diffractogram at 9.0, 11.5, 14.5,16.3, 16.5, 17.5, 17.7, 18.5, 21.0, 22.7, 24.7, 25.3 and 30.5°2θ±0.3°2θ.

In an embodiment, there is provided crystalline 5MeODMT benzoate,characterised by peaks in an XRPD diffractogram at 9.0, 11.5, 14.5,16.3, 16.5, 17.5, 17.7, 18.5, 21.0, 22.7, 24.7, 25.3 and 30.5°2θ±0.1°2θas measured by x-ray powder diffraction using an x-ray wavelength of1.5406 Å.

In an embodiment, there is provided crystalline 5MeODMT benzoate,characterised by peaks in an XRPD diffractogram at 9.0, 11.5, 14.5,16.3, 16.5, 17.5, 17.7, 18.5, 21.0, 22.7, 24.7, 25.3 and 30.5°2θ±0.2°2θas measured by x-ray powder diffraction using an x-ray wavelength of1.5406 Å.

In an embodiment, there is provided crystalline 5MeODMT benzoate,characterised by peaks in an XRPD diffractogram at 9.0, 11.5, 14.5,16.3, 16.5, 17.5, 17.7, 18.5, 21.0, 22.7, 24.7, 25.3 and 30.5°2θ±0.3°2θas measured by x-ray powder diffraction using an x-ray wavelength of1.5406 Å.

In an embodiment, there is provided crystalline 5MeODMT benzoate,characterised by peaks in an XRPD diffractogram as substantiallyillustrated in FIGS. 6, 7 or 8 .

In an embodiment, there is provided crystalline 5MeODMT benzoate,characterised by peaks in an XRPD diffractogram as substantiallyillustrated in FIG. 6 .

In an embodiment, there is provided crystalline 5MeODMT benzoate,characterised by peaks in an XRPD diffractogram as substantiallyillustrated in FIG. 7 .

In an embodiment, there is provided crystalline 5MeODMT benzoate,characterised by peaks in an XRPD diffractogram as substantiallyillustrated in FIG. 8 .

In an embodiment, there is provided crystalline 5MeODMT benzoate,characterised by one or more of:

-   Peaks in an XRPD diffractogram as previously or subsequently    described;-   An endothermic event in a DSC thermograph as previously or    subsequently described;-   An onset of decomposition in a TGA thermograph as previously or    subsequently described;-   A DVS isotherm profile as previously or subsequently described; and-   A crystalline structure as previously or subsequently described.

Example 18: Thermal Analysis of 5MeODMT Benzoate

The differential scanning calorimetry (DSC) thermograph of 5MeODMTbenzoate salt, contained one endotherm with an onset of 123.34° C., peakof 124.47° C. and an enthalpy of 134.72 J/g. There were no other thermalevents. The DSC thermograph, acquired at 10° C./min, can be seen in FIG.9 .

In an embodiment, there is provided crystalline 5MeODMT benzoate,characterised by an endothermic event in a DSC thermograph having anonset temperature of between 120 and 130° C.

In an embodiment, there is provided crystalline 5MeODMT benzoate,characterised by an endothermic event in a DSC thermograph having anonset temperature of between 120 and 130° C. as substantiallyillustrated in FIG. 9 .

In an embodiment, there is provided crystalline 5MeODMT benzoate,characterised by an endothermic event in a DSC thermograph having anonset temperature of between 120 and 130° C., between 121 and 129° C.,between 122 and 128° C., between 123 and 127° C., between 124 and 126°C.

In an embodiment, there is provided crystalline 5MeODMT benzoate,characterised by an endothermic event in a DSC thermograph having anonset temperature of between 120 and 130° C., between 121 and 129° C.,between 122 and 128° C., between 123 and 127° C., between 124 and 126°C. as substantially illustrated in FIG. 9 .

In an embodiment, there is provided crystalline 5MeODMT benzoate,characterised by an endothermic event in a DSC thermograph having anonset temperature of 123° C.

In an embodiment, there is provided crystalline 5MeODMT benzoate,characterised by an endothermic event in a DSC thermograph having anonset temperature of 123° C. a substantially illustrated in FIG. 9 .

In an embodiment, there is provided crystalline 5MeODMT benzoate,characterised by an endothermic event in a DSC thermograph having anonset temperature of 124° C.

In an embodiment, there is provided crystalline 5MeODMT benzoate,characterised by an endothermic event in a DSC thermograph having anonset temperature of 124° C. as substantially illustrated in FIG. 9 .

In an embodiment, there is provided crystalline 5MeODMT benzoate,characterised by an endothermic event in a DSC thermograph having anonset temperature of between 120 and 130° C. and a peak of between 122and 128° C.

In an embodiment, there is provided crystalline 5MeODMT benzoate,characterised by an endothermic event in a DSC thermograph having anonset temperature of between 120 and 130° C. and a peak of between 122and 128° C. as substantially illustrated in FIG. 9 .

In an embodiment, there is provided crystalline 5MeODMT benzoate,characterised by an endothermic event in a DSC thermograph having anonset temperature of between 120 and 130° C., between 121 and 129° C.,between 22 and 128° C., between 123 and 127° C. and a peak of between124 and 126° C.

In an embodiment, there is provided crystalline 5MeODMT benzoate,characterised by an endothermic event in a DSC thermograph having anonset temperature of between 120 and 130° C., between 121 and 129° C.,between 122 and 128° C., between 123 and 127° C. and a peak of between124 and 126° C. as substantially illustrated in FIG. 9 .

In an embodiment, there is provided crystalline 5MeODMT benzoate,characterised by an endothermic event in a DSC thermograph having anonset temperature of between 120 and 130° C., between 121 and 129° C.,between 122 and 128° C., between 123 and 127° C., and a peak of between124 and 126° C. and an enthalpy of between -130 and -140 J/g.

In an embodiment, there is provided crystalline 5MeODMT benzoate,characterised by an endothermic event in a DSC thermograph having anonset temperature of between 120 and 130° C., between 121 and 129° C.,between 122 and 128° C., between 123 and 127° C., and a peak of between124 and 126° C. and an enthalpy of between -130 and -140J/g assubstantially illustrated in FIG. 9 .

In an embodiment, there is provided crystalline 5MeODMT benzoate,characterised by an endothermic event in a DSC thermograph having anonset temperature of between 120 and 130° C., between 121 and 129° C.,between 122 and 128° C., between 123 and 127° C., and a peak of between124 and 126° C. and an enthalpy of between -130 and -135 J/g.

In an embodiment, there is provided crystalline 5MeODMT benzoate,characterised by an endothermic event in a DSC thermograph having anonset temperature of between 120 and 130° C., between 121 and 129° C.,between 122 and 128°C, between 123 and 127° C., and a peak of between124 and 126° C. and an enthalpy of between -130 and -135 J/g assubstantially illustrated in FIG. 9 .

The thermogravimetric analysis (TGA) thermograph of 5MeODMT benzoatesalt, revealed that the onset of decomposition was ca 131° C., which ispast the melt at ca 125° C. The TGA thermograph, acquired at 10° C./min,can be seen in FIG. 10 .

In an embodiment, there is provided crystalline 5MeODMT benzoate,characterised by an onset of decomposition in a TGA thermograph ofbetween 128 and 135° C., between 129 and 134° C., between 130 and 133°C. or between 130 and 132° C.

In an embodiment, there is provided crystalline 5MeODMT benzoate,characterised by an onset of decomposition in a TGA thermograph ofbetween 128 and 135° C., between 129 and 134° C., between 130 and 133°C. or between 130 and 132° C. as substantially illustrated in FIG. 10 .

In an embodiment, there is provided crystalline 5MeODMT benzoate,characterised by an onset of decomposition in a TGA thermograph of 131°C.

In an embodiment, there is provided crystalline 5MeODMT benzoate,characterised by an onset of decomposition in a TGA thermograph of 131°C. as substantially illustrated in FIG. 10 .

In an embodiment, there is provided crystalline 5MeODMT benzoate,characterised by one or more of:

-   an endothermic event in a DSC thermograph having an onset    temperature of between 120 and 130° C., between 121 and 129° C.,    between 122 and 128° C., between 123 and 127° C., between 124 and    126° C.; and-   an onset of decomposition in a TGA thermograph of between 128 and    135° C., between 129 and 134° C., between 130 and 133° C. or between    130 and 132° C.

In an embodiment, there is provided crystalline 5MeODMT benzoate,characterised by one or more of:

-   an endothermic event in a DSC thermograph having an onset    temperature of between 120 and 130° C., between 121 and 129° C.,    between 122 and 128° C., between 123 and 127° C., between 124 and    126° C. as substantially illustrated in FIG. 9 ; and-   an onset of decomposition in a TGA thermograph of between 128 and    135° C., between 129 and 134° C., between 130 and 133° C. or between    130 and 132° C. as substantially illustrated in FIG. 10 .

In an embodiment, there is provided crystalline 5MeODMT benzoate,characterised by one or more of:

-   an endothermic event in a DSC thermograph having an onset    temperature of 123° C.; and-   an onset of decomposition in a TGA thermograph of 131° C.

In an embodiment, there is provided crystalline 5MeODMT benzoate,characterised by one or more of:

-   an endothermic event in a DSC thermograph having an onset    temperature of between 120 and 130° C., between 121 and 129° C.,    between 122 and 128° C., between 123 and 127° C., between 124 and    126° C. and a peak of between 124 and 126° C.; and-   an onset of decomposition in a TGA thermograph of between 128 and    135° C., between 129 and 134° C., between 130 and 133° C. or between    130 and 132° C.

In an embodiment, there is provided crystalline 5MeODMT benzoate,characterised by one or more of:

-   an endothermic event in a DSC thermograph having an onset    temperature of between 120 and 130° C., between 121 and 129° C.,    between 122 and 128° C., between 123 and 127° C., between 124 and    126° C. and a peak of between 124 and 126° C. as substantially    illustrated in FIG. 9 ; and-   an onset of decomposition in a TGA thermograph of between 128 and    135° C., between 129 and 134° C., between 130 and 133° C. or between    130 and 132° C. as substantially illustrated in FIG. 10 .

In an embodiment, there is provided crystalline 5MeODMT benzoate,characterised by one or more of:

-   an endothermic event in a DSC thermograph having an onset    temperature of 123° C., a peak of 124° C.; and-   an onset of decomposition in a TGA thermograph of 131° C.

In an embodiment, there is provided crystalline 5MeODMT benzoate,characterised by one or more of:

-   an endothermic event in a DSC thermograph having an onset    temperature of 123° C., a peak of 124° C. as substantially    illustrated in FIG. 9 ; and-   an onset of decomposition in a TGA thermograph of 131° C. as    substantially illustrated in FIG. 10 .

In an embodiment, there is provided crystalline 5MeODMT benzoate,characterised by one or more of:

-   an endothermic event in a DSC thermograph having an onset    temperature of between 120 and 130° C., between 121 and 129° C.,    between 122 and 128° C., between 123 and 127° C., between 124 and    126° C., a peak of between 124 and 126° C. and an enthalpy of    between -130 and -140 J/g; and-   an onset of decomposition in a TGA thermograph of between 128 and    135° C., between 129 and 134° C., between 130 and 133° C. or between    130 and 132° C.

In an embodiment, there is provided crystalline 5MeODMT benzoate,characterised by one or more of:

-   an endothermic event in a DSC thermograph having an onset    temperature of between 120 and 130° C., between 121 and 129° C.,    between 122 and 128° C., between 123 and 127° C., between 124 and    126° C., a peak of between 124 and 126° C. and an enthalpy of    between -130 and -140 J/g as substantially illustrated in FIG. 9 ;    and-   an onset of decomposition in a TGA thermograph of between 128 and    135° C., between 129 and 134° C., between 130 and 133° C. or between    130 and 132° C. as substantially illustrated in FIG. 10 .

In an embodiment, there is provided crystalline 5MeODMT benzoate,characterised by one or more of:

-   an endothermic event in a DSC thermograph having an onset    temperature of 123° C., a peak of 124° C. and an enthalpy of -135°    C.; and-   an onset of decomposition in a TGA thermograph of 131° C.

In an embodiment, there is provided crystalline 5MeODMT benzoate,characterised by one or more of:

-   an endothermic event in a DSC thermograph having an onset    temperature of 123° C., a peak of 124° C. and an enthalpy of    -135° C. as substantially illustrated in FIG. 9 ; and-   an onset of decomposition in a TGA thermograph of 131° C. as    substantially illustrated in FIG. 10 .

A combined TGA/DSC thermograph, acquired at 10° C./min, can be seen inFIG. 11 .

Example 19: Dynamic Vapour Sorption (DVS) of 5MeODMT Benzoate

The DVS profile for 5MeODMT benzoate salt, revealed reversible wateruptake/loss over the humidity range and no hysteresis. The wateruptake/loss from 0 to 90% was gradual and amounted to a maximum of ca0.20% and was a consequence of wetting of the solid. There was noevidence of form/version modification as a consequence of exposure of5MeODMT benzoate salt to variable humidity. The DVS isotherm can be seenin FIG. 12 .

The DVS isotherm of a 5MeODMT Hydrochloride, lot 20/20/126-FP (FIG. 17 )was found to undergo significant moisture uptake upon the first sorptioncycle from 70%RH. Approximately 23%^(w) _(/w) uptake is observed between70-80%RH, whereas less than 0.3%^(w)/_(w) moisture uptake from 0-70%RHwas observed. A further 20%^(w)/_(w) moisture uptake is observed up toand when held at 90%RH before commencement of the second desorptioncycle. Subsequent sorption and desorption cycles follow a similarprofile with some observed hysteresis between operations that do notmatch the original desorption step. These return to ca. 6-9%^(w)/_(w)above the minimum mass recorded at 0%RH, which indicates significantretention of moisture. Upon completion of the DVS cycle, the inputmaterial was noted to have completed deliquesced.

A modified DVS isotherm of lot 20/45/006-FP (the same crystallineversion) was undertaken to examine material behaviour from 60%RH andabove. A 2 cycle DVS with desorption beginning from 40-0%RH withsorption from 0-60%RH in 10%RH intervals, followed by incremental 5%RHincreases to 65, 70, 75, 80 and finally 85%RH. This is to obtainin-depth profiling of the material towards humidity at these elevatedlevels.

No significant moisture uptake/loss in first desorption-sorption profilebetween 0-70%RH was noted (FIG. 18 ) followed by a ca. 0.46%w/w increasefrom 70-75%RH. A further ca. 7% uptake is observed from 75-80%RH, thenca. 40% from 80-85%w/w. Complete deliquescence of the solids wasobserved upon isolation of the material post DVS analysis, which haslikely occurred above 80%RH.

Temperature and humidity are important factors in the processing andstorage of pharmaceuticals. DVS provides a versatile and sensitivetechnique for evaluating the stability of pharmaceutical formulations.

The DVS profiles show that the stability of the benzoate salt of 5MeODMTis significantly higher than that of the hydrochloride salt and istherefore a more promising salt for development as a pharmaceuticalcomposition.

There is thus provided in an embodiment of the invention an increasedstability composition of 5MeODMT wherein the composition comprises thebenzoate salt. There is further provided a composition of 5MeODMT havingan increased stability wherein the composition comprises the benzoatesalt.

In an embodiment there is thus provided a pharmaceutical composition of5MeODMT benzoate having an increased shelf-life compared to apharmaceutical composition of 5MeODMT hydrochloride.

In an embodiment, there pharmaceutical composition may be a nasalinhalation composition.

It is advantageous that the 5MeODMT benzoate salt retains alow/consistent moisture content over its shelf-life preserving itsability to be consistently formulated, and preserving its ability to beinhaled in a free flowing powder form.

In an embodiment, there is provided crystalline 5MeODMT benzoate,characterised by a DVS isotherm profile as substantially illustrated inFIG. 12 .

In an embodiment, there is provided crystalline 5MeODMT benzoate,characterised by one or more of:

-   an endothermic event in a DSC thermograph having an onset    temperature of between 120 and 130° C., between 121 and 129° C.,    between 122 and 128° C., between 123 and 127° C., between 124 and    126° C., optionally a peak of between 124 and 126° C. and optionally    an enthalpy of between -130 and -140J/g as substantially illustrated    in FIG. 9 ;-   an onset of decomposition in a TGA thermograph of between 128 and    135° C., between 129 and 134° C., between 130 and 133° C. or between    130 and 132° C. as substantially illustrated in FIG. 10 ; and-   a DVS isotherm profile as substantially illustrated in FIG. 12 .

In an embodiment, there is provided crystalline 5MeODMT benzoate,characterised by one or more of:

-   an endothermic event in a DSC thermograph having an onset    temperature of 123° C., optionally a peak of 124° C. and optionally    an enthalpy of -135° C. as substantially illustrated in FIG. 9 ;-   an onset of decomposition in a TGA thermograph of 131° C. as    substantially illustrated in FIG. 10 ; and-   a DVS isotherm profile as substantially illustrated in FIG. 12 .

The person skilled in the art will appreciate the definingcharacteristics of one of more of the previously or subsequentlydescribed embodiments may be interchanged with those of one or moreother embodiments.

Example 20: Microscopy, Optical of 5MeODMT Benzoate

Optical microscopy examination was undertaken using an Olympus BX53Mpolarised light microscope and an Olympus SC50 digital video camera forimage capture using imaging software Olympus Stream Basic, V2.4. Theimage scale bar was verified against an external graticule, 1.5/0.6/0.01mm DIV, on a monthly basis.

A small amount of each sample was placed onto a glass slide anddispersed using mineral dispersion oil if required. The samples wereviewed with appropriate magnification and various images recorded.

Optical micrographs of 5MeODMT benzoate salt, were acquired. Thematerial is composed of large rhombohedral/trigonal crystals, rangingfrom 400 to 1000 microns. There are also small crystals adhering to thelarge crystals. Some of the small crystals, from 10 microns, are aconsequence of mechanical attrition, but others have formed bycrystallisation. There are also large aggregates composed of varioushabits. FIGS. 13 to 16 show various optical micrographs of 5MeODMTbenzoate at various magnifications.

Example 21: Further Characterisation of 5MeODMT Benzoate

The propensity of 5MeODMT benzoate to polymorphism was investigated andis considered low with solids isolated with two different XRPD patterns.

The equilibration of 5MeODMT benzoate in solvents with thermalmodulation induced a form or version change which are not considered tobe solvates.

The anti-solvent mediated crystallisation investigation of 5MeODMTbenzoate did not afford any solids indicating form or version change.

The controlled cooling crystallisation investigation of 5MeODMT benzoatedid not afford any solids indicating form or version change.

The reverse anti-solvent mediated crystallisation investigation of5MeODMT benzoate did induce a form or version change.

Two versions of 5MeODMT benzoate have been identified, the Pattern Aform (see Example 17, hereafter this form is referred to as Pattern A)version and a second, Pattern B form, believed to be meta-stable.

The equilibration investigation of 5MeODMT benzoate in a range ofsolvents with thermal modulation returned Pattern A by XRPD from mostsolvents. The equilibration solvents toluene, chlorobenzene, and anisoleinduced a form or version change in the 5MeODMT benzoate and is definedas Pattern B by XRPD. Solvate formation can be excluded based upon TGA.

The anti-solvent mediated crystallisation investigation of 5MeODMTbenzoate afforded solids which were concordant Pattern A by XRPDindicating no form or version change.

The controlled cooling crystallisation investigation of 5MeODMT benzoateafforded solids which were concordant Pattern A by XRPD indicating noform or version change.

The reverse anti-solvent mediated crystallisation investigation of5MeODMT benzoate returned Pattern A form from most mixtures. Themethanol:toluene and IPA:toluene mixtures produced material which isconsidered to be Pattern B form with improved characteristics comparedto the Pattern B form solids isolated via solvent equilibration.

XRPD examination (FIG. 19 ) revealed a powder pattern of 5MeODMTbenzoate that was concordant with that found in previous XRPDexaminations (see Example 17, Pattern A form).

DSC examination (FIG. 20 ) revealed one sharp endotherm with an onset of122.95° C. and a peak at 124.41° C. which was a match with Pattern Aform (see Example 18 wherein the onset is 123.34° C. and the peak at124.47° C.).

Additional XRPD examination of multiple lots of 5MeODMT benzoate can beseen in FIG. 21 , matching Pattern A.

DSC examination of 5MeODMT benzoate lots C1, D1 and E1 revealed a commonendothermic event with a peak temperature of 123.76° C. to 123.88° C.(FIG. 22 ). TGA analysis of C1, D1 and E1 revealed a negligible weightloss before major decomposition (FIG. 23 ).

The XRPD patterns of P1 (Toluene), Q1 (Chlorobenzene), and R1 (Anisole)revealed a new diffraction pattern referred to as ‘Pattern B’. Thesesamples contained 3 common diffractions between 18.5 and 20° 2Θ (FIG. 24).

A selection of samples of Pattern A form: C1 (IPA:Heptane [1:1]), D1(3-Methyl-1-butanol:Heptane [1:1], and E1 (TBME) were thermallycharacterised.

DSC examination of samples P1, Q1, and R1 revealed a major commonendothermic event with a peak temperature of 123.73° C. to 124.40° C.and a minor common endothermic-exothermic event between 113.01 and115.27° C.

Sample R1 contained a unique endothermic event between the minorendothermic-exothermic event and the major endotherm with a peaktemperature of 117.24° C.

TGA examination revealed a negligible weight loss for samples P1 and Q1.For sample R1 there was a weight reduction of 0.293% weight beforedecomposition. DSC thermographs of P1, Q1 and R1 at 10° C.min⁻¹ can beseen in FIG. 25 . DSC thermograph expansions of 5MeODMT benzoate lotsP1, Q1 and R1 at 10° C.min⁻¹ can be seen in FIG. 26 . TGA thermographsof 5MeODMT benzoate lots P1, Q1 and R1 at 10° C.min⁻¹ can be seen inFIG. 27 .

XRPD examination of samples P2, Q2, and R2 (thermally cycledsuspensions) revealed P2 and Q2 had converted to Pattern A form.However, R2 remained as Pattern B form but with larger diffractionsconcordant with Pattern B. The XRPD diffractogram of lots R1 and R2(thermally cycled suspensions) compared with a reference Pattern A XRPDdiffractogram can be seen in FIG. 28 .

DSC examination of P2 revealed only the major endothermic eventcharacteristic of the Pattern A form was present with a peak temperatureof 124.48° C. (FIGS. 29 - 31 ).

DSC revealed the minor endo-exotherm was smaller for sample Q2 with peaktemperatures of 113.41 and 114.32° C. but the major endotherm wasunaffected with a peak temperature of 124.23° C. (FIGS. 29 - 31 ).

DSC examination of sample R2 revealed the endothermic event in the minorendo-exotherm had two peaks of 111.53 and 113.49° C. followed by theexotherm with a peak temperature of 114.39° C., the minor events weremuch larger compared to R1 and the second minor endothermic event wasnot present (FIGS. 29 - 31 ).

TGA examination revealed a negligible weight loss for samples P2 and Q2.For sample R2 there was a weight reduction of 0.583% beforedecomposition. The increase in weight loss corresponds to the increasein the magnitude of the minor events revealed by DSC (FIGS. 29 - 31 ).

The solvent mediated equilibration of 5MeODMT benzoate with temperaturemodulation revealed the salt to be stable to version or form changeexcept for the solvents toluene, chlorobenzene, and anisole. Solidsisolated from these solvents had different XRPD patterns and thermalevents indicating a version of form change of the salt. Solvateformation can be excluded based upon TGA.

In an embodiment, there is provided crystalline 5MeODMT benzoate asdescribed above.

Anti-solvent Addition Driven Crystallisation of 5MeODMT Benzoate

Equilibration of Pattern A form in a variety of solvents and solventmixtures with thermal modulation identified a range of potentiallysuitable solvents and anti-solvents. An investigation of theanti-solvent driven crystallisation of 5MeODMT benzoate from solutionwas conducted.

5MeODMT benzoate, 6 x 220 mg, was dissolved in six solvents at 50° C.(detailed in the Table below) and the stock solutions clarified through0.45 µm syringe filters. Aliquots of each solution containing 50 mg of5MeODMT benzoate were charged to 4 crystallisation tubes.

The THF and Acetonitrile solutions of 5MeODMT benzoate crystallisedpost-clarification. All crystallisation tubes were heated to 55° C. toafford solutions and cooled to 50° C. Samples were agitated via stirrerbead at 400 rpm for the duration of the experiment.

Various anti-solvents (detailed in the Table below), 2.5 vol., werecharged to the solutions and the mixtures, then equilibrated at 50° C.for 30 minutes and the anti-solvent addition repeated.

The mixtures were cooled to 25° C. over ca. 1.5 hours and equilibratedfor 17 hours.

Suspensions were isolated via isolutes and vacuum dried for 1 minute toremove excess solvent. The isolutes were transferred to a vacuum oven at50° C. for 24 hours.

The remaining solutions were heated to 50° C. and anti-solvent, 5 vol.charged. The mixtures were equilibrated for 30 minutes and thenrepeated. Additional anti-solvent, 10 vol., was charged, equilibratedfor 30 minutes, cooled to 25° C. over 1.5 hours and equilibrated for 30minutes.

Suspensions were isolated via isolutes and vacuum dried to remove excesssolvent and then dried in a vacuum oven at 50° C. for 24 hours.

The remaining solutions were reduced to ca. 0.25 mL volume under N₂ flowat 25° C. Anti-solvent, 20 vol., was charged and the mixturesequilibrated for 30 minutes.

In an embodiment, there is provided crystalline 5MeODMT benzoate asdescribed above.

Observations with anti-solvent addition and temperature equilibration IDSolvent Anti-solvent 2.5 vol.; 50° C.; 30 mins 5 vol.; 50° C.; 30 mins25° C.; 18 hours 10 vol.; 50° C.; 30 mins 20 vol.; 50° C.; 30 mins 20vol.; 25° C.; 30 mins Reduced; 20 vol.; 30 mins A1 A2 A3 A4 MeOH 200.07mg/mL Toluene Solution Solution Solution Solution Solution SolutionSuspension Heptane Solution Solution Solution Solution Solution SolutionSuspension TBME Solution Solution Solution Solution Solution SolutionSuspension DI Water Solution Solution Solution Solution SolutionSolution Solution B1 B2 B3 B4 IPA 50.08 mg/mL Toluene Solution SolutionSolution Solution Solution Solution Suspension Heptane Solution SolutionSuspension N/a N/a N/a N/a TBME Solution Solution Solution SolutionSolution Solution Suspension DI Water Solution Solution SolutionSolution Solution Solution Solution C1 C2 C3 C4 THF 200.35 mg/mL TolueneSuspension Suspension Suspension N/a N/a N/a N/a Heptane SuspensionSuspension Suspension N/a N/a N/a N/a TBME Suspension SuspensionSuspension N/a N/a N/a N/a DI Water Solution Solution Solution SolutionSolution Solution Solution D1 D2 D3 D4 2-MeTHF 50.02 mg/mL TolueneSolution Solution Solution Solution Solution Solution Suspension HeptaneSolution Solution Solution Solution Suspension Suspension N/a TBMESolution Solution Solution Solution Solution Suspension N/a DI WaterSolution Solution Solution Solution Solution Solution Solution E1 E2 E3E4 Acetone 100.22 mg/mL Toluene Solution Solution Suspension N/a N/a N/aN/a Heptane Suspension Suspension Suspension N/a N/a N/a N/a TBMESolution Solution Suspension N/a N/a N/a N/a DI Water Solution SolutionSolution Solution Solution Solution Solution F1 F2 F3 F4 MeCN 100.25mg/mL Toluene Solution Solution Suspension N/a N/a N/a N/a HeptaneSolution Solution Suspension N/a N/a N/a N/a TBME Solution SolutionSuspension N/a N/a N/a N/a DI Water Solution Solution Solution SolutionSolution Solution Solution

Despite the initial suggestion that water was a potentially suitableanti-solvent, the utilisation of water as an anti-solvent failed toafford suspensions.

All THF, Acetone and MeCN containing mixtures (excluding water) affordedsuspensions by cooling to 25° C. with 10 volumes of anti-solvent. Allother mixtures (excluding water) either required an increasedanti-solvent charge or significant solution volume reduction andanti-solvent addition to afford suspensions.

The XRPD examination of all isolated and dried solid samples werePattern A as shown in FIGS. 32 and 33 . The XRPD characterisation of the5MeODMT benzoate solids isolated from anti-solvent mediatedcrystallisation are concordant with Pattern A. This implies that thereis no form/version modification of 5MeODMT benzoate under the conditionsinvestigated.

Controlled Cooling Crystallisation Investigation of 5MeODMT Benzoate

Observations from both the initial equilibration investigation and thefirst anti-solvent based investigations of 5MeODMT benzoate identifiedpotentially suitable solvents for the dissolution of 5MeODMT benzoate attemperature to afford saturated solutions that could then be subject toa controlled gradual cooling operation.

5MeODMT benzoate, 25±0.5 mg, was dissolved in the minimal volume ofsolvent at 50° C. (detailed in the Table below). The solutions wereclarified through a 0.45 µm Teflon syringe filter into pre-heatedcrystallisation tubes and cooled from 50° C. to -10° C. over 60 hours(1° C. Hr-1 cooling rate) and held at -10° C. for 50 hours (noagitation).

Several crystallisations contained large off-white crystals on the baseof the crystallisation tube (detailed in the Table below). The crystalswere directly transferred from the crystallisation tube to the XRPDsample holder and were left open to the atmosphere for ca. 1 hour priorto analysis.

The remaining mixtures were agitated at 400 rpm at ambient temperature,open to the atmosphere to allow partial solvent evaporation, over 18hours.

ID Solvent Solubility (mg.mL⁻¹) Observations with cooling and reductionXRPD -10° C.; 50 hours Volume reduced; 25° C.; 18 hours A MeOH 250Solution Solution N/a B IPA 42 Crystallites N/a Pattern A C THF 83Solution Suspension TBD D 2-MeTHF 31.25 Crystallites N/a Pattern A EAcetone 62.5 Crystallites N/a Pattern A F MeCN 50 Crystallites N/aPattern A G MEK 62.5 Crystallites N/a Pattern A H Nitromethane 125Crystallites N/a Pattern A I 3-methyl-1-butanol 31.25 Crystallites N/aPattern A J Chlorobenzene 12.5 Solution Suspension - K iPrOAc 12.5Solution Suspension - L MeOH:TBME (1:1) 125 Solution Solid -

XRPD examination of the solid samples isolated following cooling of thesolutions (observed as relatively large particles) revealed evidence ofpreferred orientation (FIG. 34 ).

The particle size of the samples was reduced via particle size reductionwith a mortar and pestle. Subsequent re-examination by XRPD revealed allsolids to be Pattern A (FIG. 35 ).

The XRPD characterisation of the 5MeODMT benzoate solids isolated todate from the single solvent mediated crystallisation of 5MeODMTbenzoate are concordant with Pattern A. This implies that there is noform or version modification 5MeODMT benzoate under the conditionsinvestigated.

In an embodiment, there is provided crystalline 5MeODMT benzoate asdescribed above.

Reverse Addition Anti-solvent Driven Crystallisation of 5MeODMT Benzoate

The first anti-solvent-driven crystallisation of 5MeODMT benzoate,revealed a selection of suitable solvent/anti-solvent mixtures.Utilising relatively gradual anti-solvent addition and cooling fromelevated temperature afforded only solids classed as Pattern A by XRPD.The suitable solvent/anti-solvent mixtures were re-examined with reverseaddition of hot stock solution to cold anti-solvent to potentiallyrapidly precipitate a new and/or meta-stable solid form version of5MeODMT benzoate.

5MeODMT benzoate, 165±0.5 mg, was charged to vials A to F and dissolvedin the minimal amount of solvent at 50° C. as detailed in the Tablebelow.

Anti-solvent, 1ml, was charged to crystallisation tubes then cooled to-10° C. and agitated at 400 rpm.

Aliquots of the stock solutions of 5MeODMT benzoate, ca. 50 mg, werecharged directly to the anti-solvents.

All crystallisation tubes afforded suspensions within 5 minutes ofaddition of the 5MeODMT benzoate solution.

Suspensions were isolated immediately in vacuo via isolute thentransferred to vacuum oven and dried at 50° C. for 18 hours.

TABLE - Summary of solvents, anti-solvents and observations ID SolventAnti-solvent Observations upon charging warm saturated solutions to coldanti-solvent XRPD A1 MeOH Toluene suspension within 1 minute. Pattern BA2 Heptane suspension within 1 minute. N/a A3 TBME suspension within 1minute. Pattern A B1 IPA Toluene suspension within 5 minutes. Pattern BB2 Heptane suspension within 1 minute. Pattern A B3 TBME suspensionwithin 5 minutes. Pattern A C1 THF Toluene suspension within 1 minute.Pattern A C2 Heptane Suspension upon addition Pattern A C3 TBMEsuspension within 1 minute. Pattern A D1 2-MeTHF Toluene suspensionwithin 1 minute. Pattern A D2 Heptane Suspension upon addition Pattern AD3 TBME suspension within 1 minute. Pattern A E1 Acetone Toluenesuspension within 1 minute. Pattern A E2 Heptane suspension within 1minute. Pattern A E3 TBME suspension within 1 minute. Pattern A F1 MeCNToluene suspension within 1 minute. Pattern A F2 Heptane Precipitateupon addition Pattern A F3 TBME suspension within 1 minute. Pattern A

XRPD examination of most isolated solids (except for A1 and B1) wereconcordant with Pattern A (see FIGS. 36 and 37 ).

XRPD examination of solids A1 and B1 were concordant with one anotherbut not Pattern A (FIGS. 38, 39 )

Lots A1 and B1 shared diffractions with 5MeODMT benzoate lot Q1 (apattern previously identified as Form B). However, on closer inspection,Q1 was observed to share diffractions with Pattern A. As lot Q1 shareddiffractions with both lots A1 and B1 and Pattern A.

The diffraction patterns for lots A1 and B1 were considered to becharacteristic of Pattern B.

The DSC thermograph of sample A1 (FIG. 41 ) revealed an endothermicevent with onset ca. 110° C. and major peak at 113.98° C., followed byan exotherm with onset 114.72° C. and peak at 116.42° C., followed by asecond endotherm with an onset of 123.00° C. and peak at 123.72° C.

DSC examination of sample B1 (FIG. 42 and FIG. 43 ) revealed a similarDSC thermograph to A1 but the first endothermic event was larger, 108J.g⁻¹ compared 90 J.g⁻¹ and only contained 2 peak temperatures of 109.00and 110.32° C. instead of the 3 present in A1. The exothermic event thatimmediately followed was smaller, 17 J.g⁻¹ compared to 41 J.g⁻¹. Thesecond main endotherm was also smaller for B1 at 38 J.g⁻¹ compared to 80J.g⁻¹ for A1.

In an embodiment, there is provided crystalline 5MeODMT benzoate asdescribed above.

In an embodiment, there is provided crystalline 5MeODMT salt,characterised by an endothermic or exothermic event in a DSC thermographas substantially illustrated in any one of the Figures.

In an embodiment, there is provided a composition comprising 5MeODMTbenzoate Pattern A form.

In an embodiment, there is provided a composition comprising 5MeODMTbenzoate Pattern B form.

In an embodiment, there is provided a composition comprising a mixtureof 5MeODMT benzoate Pattern A form and Pattern B form.

Example 22: Generation of the Amorphous 5MeODMT Benzoate Rapid in VacuoConcentration

5MeODMT benzoate, 101.55 mg, was dissolved in THF, 4 mL and clarifiedinto a 100 mL round bottom flask. The solution was concentrated in vacuo40° C. at 200 rpm. The liquid evaporated from the flask, yielding aconcentrated clear colourless liquid residue around the flask.

The residue was dissolved in acetone, 4ml, concentrated in vacuo at 40°C. at 200 rpm. The liquid evaporated from the flask, yielding aconcentrated clear colourless liquid residue around the flask. Smallcrystals were visible on the inside of the flask, these were isolatedafter 18 hours affording 21-01-051 A.

Quench of Melt

5MeODMT benzoate was held at 125° C. for 5 minutes by TGA then cooled toambient over 3 minutes affording 21-01-051 B. The sample was analysedimmediately and after 20 hours held in a sealed container.

Lyophilisation

5MeODMT benzoate, 200 mg, was dissolved in deionised water, 10 ml, andclarified through a 0.45 µm nylon filter into a 500 mL round bottomflask, then frozen into a thin layer. The flask was transferred to avacuum and equilibrated to ambient temperature affording a fluffy whitesolid, 21-01-051 C.

The solid transformed into gum over ca. 1 hour. The sample was analysedimmediately and after 20 hours held in a sealed container.

Lyophilisation for Amorphous Solid Equilibration

Lyophilisation was repeated as described above with 5MeODMT benzoate,800 mg, dissolved in 25 ml, affording 21-01-051 D. The solid was heatedto 60° C. for 10 minutes then cooled yielding 21-01-051 E. The samplewas analysed immediately.

FIG. 44 shows XRPD comparison of 5MeODMT benzoate lot 21-01-051 A, E, EParticle size reduced and Pattern A reference.

FIG. 45 shows XRPD of 5MeODMT benzoate lot 21-01-051 B, obtained fromquenching the melt.

FIG. 46 shows XRPD of 5MeODMT benzoate lot 21-01-051 C, obtained bylyophilisation.

The XRPD patterns of 5MeODMT benzoate 21-01-051 B and C were concordantwith Pattern A, indicating that the amorphous form converts to Pattern Aform in a sealed container at ambient temperature and pressure.

The XRPD pattern of 5MeODMT benzoate 21-01-051 A, the solid isolated byacetone concentration, was concordant with Pattern A form. Rapid invacuo concentration did not produce the amorphous version.

The XRPD patterns revealed 5MeODMT benzoate 21-01-051 B and C to have anamorphous ‘halo’, indicating quenching molten material andlyophilisation produced amorphous 5MeODMT benzoate.

FIG. 47 shows XRPD comparison of 5MeODMT benzoate lot 21-01-051 B after20 hours, C after 20 hours, and Pattern A reference.

The XRPD pattern of 5MeODMT benzoate 21-01-051 E were concordant withPattern A, indicating that the amorphous form converts to Pattern A format 60° C. for 10 minutes.

FIG. 48 shows XRPD comparison of 5MeODMT benzoate lot 21-01-051 A, E, Eparticle size reduced, and Pattern A reference.

DSC examination revealed amorphous 5MeODMT benzoate 21-01-051 C and Dobtained by lyophilisation, contained an exothermic event with a peaktemperature between 65.63 and 70.84° C., followed by a broad endothermicshoulder leading into a endothermic event with a peak temperaturebetween 120.20 and 121.22° C. The major endothermic event is ca. 3° C.lower compared to Pattern A form material.

FIG. 49 shows DSC thermograph comparison of 5MeODMT benzoate lot21-01-051 A, C, and D at 10° C.min⁻¹, isolated from acetone concentrate,051 A, and lyophilisation, 051 C and 051 D.

DSC examination revealed 5MeODMT benzoate 21-01-051 C post 20 hours nolonger contained an exothermic event and the endothermic event at ca.123° C. was sharper and concordant with Pattern A form.

FIG. 50 shows DSC thermograph comparison of 5MeODMT benzoate lot21-01-051 C and C post 20 hours at 10° C.min⁻¹.

Amorphous 5MeODMT benzoate can be generated by lyophilisation of anaqueous solution and the quenched melt.

The amorphous 5MeODMT benzoate will convert to Pattern A form materialon standing.

In one embodiment, there is provided an amorphous 5MeODMT benzoate. Inone embodiment, there is provided a composition comprising an amorphous5MeODMT benzoate.

In one embodiment, there is provided a composition comprising anamorphous 5MeODMT benzoate salt produced as detailed above or below.

Example 23: Further Characterisation of Amorphous 5MeODMT Benzoate

The thermal examination of amorphous 5MeODMT benzoate by DSC and hotstage microscopy revealed a crystallisation event and endothermic melt.The endothermic melt is not consistent with the DSC thermograph ofPattern A form.

The solvent mediated equilibration of amorphous 5MeODMT benzoate withthermal modulation afforded Pattern A by XRPD and DSC from all solventsexcept anisole. New variations were generated.

Amorphous 5MeODMT benzoate generated by lyophilisation, 21-01-051 D(21-01-051) was examined by hot-stage microscopy at a heating rate of 5°C.min-1 for corroboration with the DSC thermograph of the amorphoussolid.

Initially, 5MeODMT benzoate was a sticky translucent gum (FIG. 52 ) thatupon heating to 54.21° C. reduced in viscosity and spread out into athinner uniform layer (FIG. 53 ). At 54.21° C. the liquid began tocrystallise (FIG. 53 ) which neared completion by 74.21° C. (FIG. 54 ).The newly formed crystals began to melt at 114.24° C. (FIG. 55 ) whichneared completion by 120.14° C. (FIG. 56 ).

The hot stage microscopy examination corroborated with events in the DSCthermograph (FIG. 51 ); the crystallisation exotherm at ca. 65° C. andthe melt endotherm at ca. 115° C.

FIG. 51 shows DSC thermograph of 5MeODMT benzoate lot 21-01-051 D, largescale lyophilised material, with temperature stamps corresponding tohot-stage microscopy images.

FIG. 52 shows Micrograph image of 5MeODMT benzoate lot 21-01-051 D at30.02° C.

FIG. 53 shows Micrograph image of 5MeODMT benzoate lot 21-01-051 D at54.21° C.

FIG. 54 shows Micrograph image of 5MeODMT benzoate lot 21-01-051 D at74.21° C.

FIG. 55 shows Micrograph image of 5MeODMT benzoate lot 21-01-051 D at114.23° C.

FIG. 56 shows Micrograph image of 5MeODMT benzoate lot 21-01-051 D at120.14° C.

Solvent Mediated Equilibration of Amorphous 5MeODMT Benzoate WithThermal Manipulation

The action of agitating the amorphous version of a solid in a series ofsolvents can lead to dissolution and crystallisation to more ordered andenergetically stable solids. In this manner, alternate crystal forms ofa solid can be potentially generated for comparison and evaluation.

Amorphous 5MeODMT benzoate 21-01-51 D, 24x 25 ±2 mg was transferred tocrystallisation tubes and solvent, 0.125 mL. The mixtures were agitatedat 300 rpm at 25° C. for 30 minutes. Solvent, 0.125 mL, was charged torelevant mixtures and equilibrated for 18 hours.

Mixtures were heated to 55° C. for 8 hours then cooled to 25° C. over 1hour then equilibrated for 18 hours at 300 rpm.

Suspensions were transferred to Isolute tubes for isolation and driedunder vacuum for 2 mins then dried in vacuo at 50° C. for 24 hours.

XRPD examination of the solids isolated from the equilibration ofamorphous 5MeODMT benzoate with thermal modulation revealed all powderpatterns to be concordant with Pattern A (FIG. 57 and FIG. 58 ).

FIG. 57 shows XRPD pattern comparison of 5MeODMT benzoate lot 21-01-054solids isolated from the equilibration of amorphous 5MeODMT benzoatewith thermal modulation.

FIG. 58 shows XRPD pattern comparison of 5MeODMT benzoate lot 21-01-054M isolated from the equilibration of amorphous 5MeODMT benzoate inα,α,α-trifluorotoluene with thermal modulation with lot 20-37-64(Pattern A).

The DSC examination of a selection of 5MeODMT benzoate solids classifiedas Pattern A revealed a major endothermic event with onset temperaturesbetween 121.88 and 123.39° C. and peak temperatures between 123.66 and124.11° C. This endotherm is characteristic of Pattern A form (FIG. 59).

5MeODMT benzoate 21-01-054 Q, solid isolated from anisole, containedevents within the major endothermic event with peak temperatures of111.64° C. and 116.92° C. (FIG. 60 , FIG. 61 ). This is in line with theDSC thermograph of 5MeODMT benzoate isolated following equilibration inanisole, 20-37-64-R1, although less pronounced.

FIG. 59 shows DSC thermograph comparison of a selection of 5MeODMTbenzoate lot 21-01-054 solids isolated from the equilibration ofamorphous 5MeODMT benzoate with thermal modulation classified as PatternA form.

FIG. 60 shows DSC thermograph expansion comparison of a selection of5MeODMT benzoate lot 21-01-054 solids isolated from the equilibration ofamorphous 5MeODMT benzoate with thermal modulation classified as PatternA form, highlighting an event in lot 21-01-054 Q, solid isolated fromanisole.

FIG. 61 shows Expanded DSC thermograph expansion highlighting an eventin lot 21-01-054 Q, isolated from anisole.

Example 24: Pattern C

Additional 5MeODMT benzoate Pattern B form material was required forfurther characterisation. The procedure of charging 5MeODMT benzoate/IPAsolution to cold toluene was employed.

5MeODMT benzoate 20/20/150FP2, 250 mg, was dissolved in IPA, 5ml, andheated to 50° C. and clarified. The clarified solution, 2x 2ml, 100 mgof 5MeODMT benzoate, was charged to toluene, 4ml, at -10° C. andagitated at 750 rpm.

Upon addition, both mixtures remained as clear colourless solutions.

After 30 minutes a solid had formed in tube A. The solid, 21-01-060 A,was isolated immediately via isolute and dried in vacuo for 2 minutes. Aportion, 21-01-060 A1 was removed for XRPD analysis, a portion was driedin vacuo at 50° C. for 20 hours, 21-01-060 A2.

After 50 minutes a solid had formed in tube B and was allowed toequilibrate at -10° C. and agitated at 750 rpm for 3 hours. The solid,21-01-060 B, was isolated immediately via isolute and dried in vacuo for2 minutes. A portion 21-01-060 B1 was removed for XRPD analysis, theremainder was dried in vacuo at 50° C. for 20 hours, 21-01-060 B2.

Sample 5MeODMT benzoate 21-01-060 A1 and A2 5MeODMT benzoate 21-01-060B1 and B2 Tube 21-01-060 A 21-01-060 B Origin Reverse anti-solventaddition of salt/IPA solution to toluene at -10° C. Time to formsuspension 30 minutes 50 minutes Time left as suspension ca. 0 minutes 3hours Analysis XRPD pattern collected taken after 0 hours air dried XRPDpattern and DSC thermograph collected after 1 hour air dried None XRPDpattern and DSC thermograph collected after 20 hours air drying XRPDpattern and DSC thermograph collected after 20 hours drying in vacuo at50° C.

Samples 21-01-060 A1 and 21-01-060 B1 were air dried under ambientconditions for 20 hours and assessed by XRPD and DSC.

Immediately following isolation, 21-01-060 A1 was analysed by XRPD. Thisrevealed a new diffraction pattern that was not concordant with PatternA or Pattern B. This is referred to as Pattern C.

The XRPD pattern of 21-01-060 A1 (2 mins air dried) was reacquiredfollowing a further 1 hour of air drying under ambient conditions (FIG.62 ). Additional diffractions were present in the XRPD of 21-01-060 A1(air dried 1 hour) compared to 21-01-060 A1 (2 mins air dried), whichsuggests conversion to Pattern B form (FIG. 63 ).

FIG. 62 shows XRPD pattern comparison of 5MeODMT benzoate lot 21-01-060A1 air dried 2 minutes, lot 21-01-049 B1, Pattern B, and lot 20-37-64,Pattern A.

FIG. 63 shows XRPD pattern comparison of 5MeODMT benzoate lot 21-01-060A1-air dried 1 hour and lot 21-01-060 A1-air dried 2 minutes.

FIG. 64 shows XRPD pattern comparison of 5MeODMT benzoate lot 21-01-060A1-air dried 2 minutes, lot 21-01-060 A1-air dried 1 hour, and lot21-01-049 B1, Pattern B.

The DSC thermograph of 5MeODMT benzoate 21-01-060 A1 (air dried 1 hour)(FIG. 65 and FIG. 66 ) revealed a minor broad endotherm with a peaktemperature of 108° C. which is considered characteristic of Pattern Cform solid.

This is followed by an exotherm with a peak temperature of 112.35° C.which is considered to be the conversion of Pattern C form to Pattern Aform, since the main endotherm has a peak temperature of 124.12° C.,which is characteristic of Pattern A form.

FIG. 65 shows DSC thermograph of 5MeODMT benzoate lot 21-01-060 A1,isolated immediately from IPA/toluene and air dried for 1 hour.

FIG. 66 shows DSC thermograph expansion of 5MeODMT benzoate lot21-01-060 A1, isolated immediately from IPA/toluene and air dried for 1hour.

An XRPD pattern of 5MeODMT benzoate lot 21-01-060 A1 was acquiredfollowing a total of 20 hours air drying. This revealed the pattern(FIG. 67 ) to be concordant with SPS5520 21-01-049 B1, Pattern B, butcontained diffractions indicative of Pattern C such as 10.3° 2Θ (FIG. 67).

FIG. 67 shows XRPD pattern comparison of 5MeODMT benzoate lot 21-01-060A1 air dried 20 hours, lot 21-01-060 A1 air dried 2 minutes, and lot21-01-049 B1, Pattern B ref.

5MeODMT Benzoate 21-01-060 B1 Produced From Reverse Anti-solventAddition, Equilibrated for 3 Hours, Then isolated and air drying atambient temperature

Immediately following isolation, the solid was analysed by XRPD. Thisrevealed a diffraction pattern concordant with 21-01-060 A1, Pattern C(FIG. 68 ).

The XRPD pattern (FIG. 69 ) was reacquired following 20 hours air dryingand revealed the solid was still Pattern C but contained diffractions at17.2° and 19.5 2Θ indicative of Pattern B.

FIG. 68 shows XRPD pattern comparison of 5MeODMT benzoate lot 21-01-060B1, isolated after 3 hours equilibration then air dried for 2 mins andA1 isolated immediately then air dried for 2 minutes.

FIG. 69 shows XRPD pattern comparison of 5MeODMT benzoate lot 21-01-060B1, isolated after 3 hours equilibration then air dried for 20 hours andB1 isolated after 3 hours equilibration then air dried for 2 minutes,and lot 21-01-049 B1, Pattern B.

Example 25: Investigation of the Impact of Solvent Vapour Diffusion UponAmorphous 5MeODMT Benzoate

Subjecting an amorphous solid to solvent vapour is considered to be alow energy process for inducing form or version change of the solid inorder to generate meta stable versions and/or solvates from theamorphous solid for comparison and evaluation.

5MeODMT benzoate, 497.44 mg, was dissolved in deionised water, 10 mL,and clarified into a 500 mL round bottom flask and lyophilised asdetailed previously. The fluffy white solid produced, 12x 25 mg, wascharged to HPLC vials and placed in a sealed container with ca. 2 mL ofsolvent. The solvents employed and observations are detailed in theTable below.

Following equilibration for 7 days, solids were transferred to XRPDsample holder directly and analysed by XRPD. DSC was collected for allnotable samples by XRPD and a selection of Pattern A form solids.

ID Solvent Observations Upon charge Post 1 day Post 7 days A MethanolOff-white gum White Opaque solid Yellow solution B Ethyl acetateOff-white gum Off-white gum Off-white agglomerate C Acetone Off-whitegum White Opaque solid Solids adhered to glass above a clear solution DAnisole Off-white gum Off-white gum Off-white agglomerate E TBMEOff-white gum Off-white gum Off-white agglomerate F THF Off-white gumOff-white gum Off-white agglomerate G Toluene Off-white gum Off-whitegum Off-white agglomerate H 1,4-Dioxane Off-white gum Off-white gumOff-white agglomerate I DCM Off-white gum Off-white gum Solids adheredto glass above a clear solution J Heptane Off-white gum Off-white gumOff-white agglomerate K Acetonitrile Off-white gum Off-white gumOff-white agglomerate L Water Off-white gum Off-white gum Off-whiteagglomerate

XRPD pattern for all samples (FIG. 70 ) except for 21-01-058 D and21-01-058 G, isolated from anisole and toluene respectively, wereconcordant with Pattern A form material (FIG. 71 ).

FIG. 70 shows XRPD pattern comparison of 5MeODMT benzoate lot 21-01-058solids isolated from amorphous 5MeODMT benzoate exposed to solventvapour.

FIG. 71 shows XRPD pattern comparison of 5MeODMT benzoate lot 21-01-058K, isolated from amorphous 5MeODMT benzoate exposed to solvent vapour,with lot 20-37-64, Pattern A.

The DSC thermograph comparison of a selection of Pattern A form solids(FIG. 72 ) revealed an endothermic event with peak temperatures between123.69° C. and 124.14° C. which is indicative of Pattern A form andcorroborates the XRPD data.

The DSC thermograph of lot 21-01-058 G (not Pattern A form, by XRPD)demonstrates a minor endothermic event prior to the main endotherm andis elaborated on below.

FIG. 72 shows DSC thermograph comparison of 5MeODMT benzoate lot21-01-058 B, lot 21-01-058 F, lot 21-01-058 K, and lot 21-01-062 G.

Example 26: Pattern D 5MeODMT Benzoate 21-01-058 D, Solid Isolated FromExposure of Amorphous 5MeODMT Benzoate to Anisole Vapour for 7 days

XRPD of 5MeODMT benzoate lot 21-01-058 D, isolated from amorphous5MeODMT benzoate exposed to anisole vapour, revealed a unique powderpattern (FIG. 73 and FIG. 74 ). The diffractions of 21-01-058 D aresimilar to Pattern C but vary in intensity and position (FIG. 75 ).

FIG. 73 shows XRPD pattern comparison of 5MeODMT benzoate lot 21-01-058D, lot 20-37-64, Pattern A, lot 21-01-049 B1, Pattern B, and lot21-01-060 B1, Pattern C (air dried 20 hours).

FIG. 74 shows XRPD pattern comparison of 5MeODMT benzoate lot 21-01-058D, lot 21-01-049 B1, Pattern B, and lot 21-01-060 B1, Pattern C (airdried 20 hours).

FIG. 75 shows XRPD pattern expansion comparison of 5MeODMT benzoate lot21-01-058 D, lot 21-01-049 B1, Pattern B, and lot 21-01-060 B1, PatternC (air dried 20 hours).

The DSC thermograph of 5MeODMT benzoate lot 21-01-058 D (FIG. 76 ),isolated from amorphous 5MeODMT benzoate exposed to anisole vapourrevealed an endothermic event with a peak temperature of 118.58° C. Thiscorroborates the XRPD data, confirming a new version has been isolated.

FIG. 76 shows DSC thermograph of 5MeODMT benzoate lot 21-01-058 D,isolated from exposure of anisole vapour to amorphous form.

Amorphous 5MeODMT benzoate exposed to anisole vapour afforded an anisolehemi-solvate, nominated herein as Pattern D form. The XRPD pattern ofPattern D form is similar to Pattern C, the toluene hemi-solvate, butwith variance in peak position.

Amorphous 5MeODMT benzoate exposed to toluene vapour afforded a mixedform version that was predominantly Pattern A form with some evidence ofPattern C form, the toluene hemi-solvate, observed by XRPD and DSC.

Amorphous 5MeODMT benzoate exposed to all other solvent vapours returnedexclusively Pattern A by XRPD and DSC.

Sample Solvent XRPD DSC 1H NMR A Methanol N/A - solution by day 7 BEthyl acetate Pattern A Endo at 123.69° C. NC C Acetone Pattern A NC NCD Anisole Pattern D Endo at 118.58° C. Salt to anisole ratio of 1:0.47 ETBME Pattern A NC NC F THF Pattern A Endo at 123.84° C. NC G ToluenePredominantly Pattern A and some Pattern C Endo at 114.39° C. Endo at124.14° C. Salt to toluene ratio of 1:0.04 H 1,4-Dioxane Pattern A NC NCI DCM Pattern A NC NC J Heptane Pattern A NC NC K Acetonitrile Pattern AEndo at 123.85° C. NC L Water Pattern A NC NC

Example 27: Pattern E

5MeODMT benzoate Pattern C form was isolated via reverse anti-solventaddition of isopropanol solution of 5MeODMT benzoate to toluene, thissolid is believed to be a hemi-solvate which when desolvated affordedPattern B form. Pattern B form has been accessed by equilibration of5MeODMT benzoate in anisole and chlorobenzene. Pattern B form may beaccessed from anisole and chlorobenzene hemi-solvates, consequentlyreverse anti-solvent addition to chlorobenzene and anisole is believedto afford a hemi-solvate as with toluene.

5MeODMT benzoate 20/20/150FP2, 650 mg, was charged to sample vial withIPA, 13 ml, and heated to 50° C. The clear solution was clarifiedthrough a 0.45 µm nylon syringe filter.

Anti-solvent, 4ml, was charged to crystallisation tubes and cooled to-10° C. with agitation via stirrer bead at 750 rpm as detailed in theTable below.

IPA stock solution at 50° C., 2ml, was charged to cold anti-solvent, 4ml, at -10° C.

Observations are detailed in the Table below, with B, D, and F isolatedimmediately.

Tubes A, C, and E were equilibrated for 3 hours then isolated.

Suspensions were transferred to isolute cartridge and dried in vacuo forNMT 60 seconds and analysed immediately, following 4 hours, and 44 hoursopen to atmosphere.

5MeODMT benzoate 21-01-064 E was damp after air drying for 60 seconds.

Tube Anti-solvent Time to form a suspension Equilibration period aftersuspension formed A Toluene 3.5 hours 3 hours B Toluene 3 hours 0 hoursC Chlorobenzene 3.5 hours 3 hours D Chlorobenzene 3.5 hours 0 hours EAnisole 3.5 hours 3 hours F Anisole 3 hours 0 hours

5MeODMT benzoate 21-01-064 D was isolated immediately following theformation of the suspension afforded by the addition of concentrated IPAsolution to chlorobenzene at -10° C.

The XRPD revealed the diffraction pattern of 5MeODMT benzoate lot21-01-064 D was similar to 21-01-060 B1 (air dried 2 minutes), Pattern C(FIG. 77 ). Several diffractions including 19 and 20° 2Θ are slightlyhigher and lower compared to Pattern C which are not consequences of thesample presentation (FIG. 78 ).

5MeODMT benzoate lot 21-01-064 D is a new diffraction pattern, anddefined herein as Pattern E.

FIG. 77 shows XRPD pattern comparison of 5MeODMT benzoate lot 21-01-064D, and 21-01-060 B1 (air dried 2 minutes).

FIG. 78 shows XRPD pattern expansion comparison of 5MeODMT benzoate lot21-01-064 D, and 21-01-060 B1 (air dried 2 minutes).

The DSC thermograph of 5MeODMT benzoate lot 21-01-064 D revealed a majorbimodal endothermic event with peak temperatures of 110.31° C. and113.13° C. (FIG. 79 ), followed by a minor endothermic event with a peaktemperature of 119.09° C.

FIG. 79 shows DSC thermograph of 5MeODMT benzoate lot 21-01-064 D at 10°C.min-1.

The 1H NMR spectrum of 5MeODMT benzoate lot 21-01-064 D isolatedimmediately following equilibration revealed the stoichiometry of thesalt to be 1:1 and also revealed a salt to solvent ratio forchlorobenzene of 1:0.512 and a salt to solvent ratio for IPA of 1:0.013.

The isolated salt is a chlorobenzene hemi-solvate.

There is no evidence of a Pattern A form endothermic at ca. 123° C. inthe DSC thermograph, 21-01-064 D (FIG. 79 ) since it is considered thatthe residual chlorobenzene is inhibiting crystallisation of 5MeODMTbenzoate.

5MeODMT benzoate 21-01-064 C was isolated following a 3 hourequilibration of the suspension afforded by the addition of concentratedIPA solution to chlorobenzene at -10° C.

The XRPD revealed the diffraction pattern of 5MeODMT benzoate lot21-01-064 C was concordant with 21-01-064 D, Pattern E (FIG. 80 ).

FIG. 80 shows XRPD pattern comparison of 5MeODMT benzoate lot 21-01-064C, and 21-01-064 D.

FIG. 81 shows XRPD pattern expansion comparison of 5MeODMT benzoate lot21-01-064 C, and 21-01-064 D.

The DSC thermograph of 5MeODMT benzoate lot 21-01-064 C revealed a majorendothermic event with peak temperatures of 111.39° C., 113.22° C., and114.35° C. (FIG. 82 ).

The DSC thermograph of 21-01-064 C is similar to that of the thermographof 21-01-064 D.

FIG. 82 shows DSC thermograph of 5MeODMT benzoate lot 21-01-064 C at 10°C.min-1.

The 1H NMR spectrum of 5MeODMT benzoate lot 21-01-064 C isolatedfollowing a 3 hour equilibration revealed the stoichiometry of the saltto be 1:1 and also revealed a salt to solvent ratio for chlorobenzene of1:0.506 and a salt to solvent ratio for IPA of 1:0.004.

The isolated salt is a chlorobenzene hemi-solvate.

The XRPD of 5MeODMT benzoate lot 21-01-064 C (4 hours air dried)revealed a diffraction pattern concordant with 21-01-064 C, Pattern E.

The XRPD of 5MeODMT benzoate lot 21-01-064 C (44 hours air dried)revealed a diffraction pattern concordant with 21-01-064 C and 21-01-064C (4 hours air dried), Pattern E.

The XRPD of 5MeODMT benzoate lot 21-01-064 F revealed a diffractionpattern concordant with 21-01-058 D, Pattern D from the vapour diffusioninvestigation of amorphous 5MeODMT benzoate in anisole, but morecrystalline and does not contain minor diffractions characteristic ofPattern A.

The XRPD of 5MeODMT benzoate 21-01-064 E revealed a diffraction patternconcordant with 21-01-064 F, Pattern D.

The XRPD of 5MeODMT benzoate 21-01-064 E (air dried 4 hours) revealed adiffraction pattern concordant with 21-01-064 E, Pattern D.

The XRPD of 5MeODMT benzoate 21-01-064 E (air dried 44 hours) revealed adiffraction pattern concordant with 21-01-064 E, Pattern D but with anadditional diffraction at 18.3° 2Θ, which is believed to be anindication of Pattern B.

Example 28: Further Discussion of Patterns B to E Pattern B

Below is a Table which summarises lots of 5MeODMT benzoate withpredominantly Pattern B form compositional and crystallographiccharacteristics.

Sample name Comments Crystalline character Composition by 1H NMR 5MeODMTbenzoate 21-01-049 A1 Addition of methanol solution to cold toluene thenisolated and dried in vacuo at 50° C. Pattern B and C 1:0.03 toluene 0MeOH 5MeODMT benzoate 21-01-049 B1 Addition of IPA solution to coldtoluene then isolated and dried in vacuo at 50° C. Pattern B 1:0.01toluene 0 IPA 5MeODMT benzoate 21-01-047 J Crystallised from cooling asaturated solution of chlorobenzene and dried in vacuo at 50° C. PatternB and A 5MeODMT benzoate 21-01-060 A1 (air dried 20 hours) Addition ofIPA solution to cold toluene then isolated immediately and air dried for20 hours Pattern B and C 1:0.04 toluene 1:0.20 IPA 5MeODMT benzoate21-01-060 A2 Addition of IPA solution to cold toluene then isolatedimmediately and dried in vacuo at 50° C. Pattern B 1:0.007 toluene1:0.09 IPA 5MeODMT benzoate 21-01-060 B2 Addition of IPA solution tocold toluene, equilibrated for 3 hours, then isolated and dried in vacuoat 50° C. Pattern B and C 1:0.05 toluene 1:0.07 IPA

Below is a Table which summarises predominantly Pattern B thermalcharacteristics.

Sample name Broad exo at 101° C. Endo at 109.5° C. Endo at 110.5° C.Endo at 113° C. Exo at 113.4° C. Endo at 114° C. Exo at 114.1° C. Exo at117.8° C. Endo at 124° C. 5MeODMT benzoate 21-01-049 A1 Y Y Y Y Y5MeODMT benzoate 21-01-049 B1 Y Y Y Y 5MeODMT benzoate 21-01-047 J Y Y YY 5MeODMT benzoate 21-01-060 A1 (air dried 20 hours) Y Y Y 5MeODMTbenzoate 21-01-060 A2 Y Y Y Y 5MeODMT benzoate 21-01-060 B2 Y Y YCharacteristic of Pattern B Characteristic of Pattern A

5MeODMT benzoate lot 21-01-049 B1 was produced via reverse anti-solventaddition of an IPA solution to toluene, isolated immediately, then driedin vacuo at 50° C. XRPD revealed a diffraction pattern that was definedas Pattern B. DSC examination identified an endothermic event at 110° C.which coincides with the boiling point of toluene, this is followed byan endothermic event immediately followed by an exothermic eventindicating the melt-crystallisation of Pattern B form to Pattern A formthen the endothermic event indicating the melt of Pattern A formmaterial. 1H NMR revealed low amounts of residual toluene and no IPA.

5MeODMT benzoate lot 21-01-060 A2 was produced by the same methodologyas 049 B1 except on a larger scale and afforded an identical product byXRPD and DSC but contained residual IPA by 1H NMR.

5MeODMT benzoate lot 21-01-049 A1 was produced by the same methodologyas 049 B1 except it was initially dissolved in methanol, XRPD revealed apowder pattern concordant with Pattern B with some Pattern C. 1H NMRrevealed a salt to toluene ratio of 1:0.03. DSC examination revealed asimilar thermograph to 049 B1 but the first endothermic event at 110° C.was larger and the subsequent endothermic melt of Pattern B form isbimodal and peaks at a lower temperature. Following the melt of PatternB form, Pattern A form crystallises, and melts as expected.

5MeODMT benzoate lot 21-01-060 B2 was produced by the same methodologyas 060 A2 but equilibrated for 3 hours before isolation and drying invacuo. XRPD revealed a mixture of Pattern B with some Pattern C. 1H NMRrevealed a salt to toluene ratio of 1:0.05. DSC examination revealed asimilar thermograph to 049 A1 (a mixture of Pattern B and C forms) butthe Pattern B form melt endothermic event is not bimodal. Theendothermic event at 110° C. is considered to be a consequence of aslightly increased amount of toluene in the sample in the form of thetoluene hemi-solvate.

5MeODMT benzoate lot 21-01-060 A1 (air dried 20 hours) was produced bythe same methodology as 060 A2 but was air dried instead of at 50° C. invacuo. XRPD revealed a mixture of Pattern B and C. 1H NMR revealed asalt to toluene ratio of 1:0.04. However, 060 A1 contained a significantamount more IPA than other samples (1:0.2 instead of 1:0.05). This mayhave modified the endothermic events during the DSC examination of thesample, but the Pattern A form melt endothermic event is present.

5MeODMT benzoate lot 21-01-047 J was produced by crystallisation fromchlorobenzene at 50° C. and dried in vacuo at 50° C. XRPD revealed thesample to be a mixture of Pattern B and some Pattern A. DSC examinationrevealed an endothermic event similar to the endothermic eventconsidered to be loss of toluene, which is believed to indicate the lossof chlorobenzene. The melting endotherm of Pattern B form occurs earlierthan for 049 B1 but the crystallisation of Pattern A form is veryexothermic and is accompanied by a melt of Pattern A form.

5MeODMT benzoate Pattern B form material contains a characteristicendo-exothermic event as it melts then crystallises as Pattern A form,Pattern B form is produced by the desolvation of hemi-solvates,therefore an endothermic event characteristic of the residualhemi-solvate is present in all samples isolated.

For those solids that contain toluene at low levels, which is believedto be the hemi-solvate version of the salt, the thermal characteristicswill be modified by the loss of toluene.

Pattern C

Below is a Table which summarises lots of 5MeODMT benzoate withpredominantly Pattern C compositional and crystallographiccharacteristics.

Sample name Comments Crystalline character Composition by 1H NMR 5MeODMTbenzoate 21-01-060 A1 (air dried 1 hour) Addition of IPA solution tocold toluene then isolated and air dried for 1 hour Pattern C and B5MeODMT benzoate 21-01-060 B1 (air dried 20 hours) Addition of IPAsolution to cold toluene, equilibrated for 3 hours, then isolated andair dried for 20 hours Pattern C and B 1:0.43 toluene 1:0.12 IPA 5MeODMTbenzoate 21-01-064 A Addition of IPA solution to cold toluene,equilibrated for 3 hours, then isolated Pattern C 1:0.49 toluene 1:0.004IPA 5MeODMT benzoate 21-01-064 A (air dried 4 hours) (DSC at 2.5°C.min⁻¹) Addition of IPA solution to cold toluene, equilibrated for 3hours, then isolated and air dried for 4 hours Pattern C and B 5MeODMTbenzoate 21-01-064 A (air dried 44 hours) Addition of IPA solution tocold toluene, equilibrated for 3 hours, then isolated and air dried for44 hours Pattern C and B 5MeODMT benzoate 21-01-064 B Addition of IPAsolution to cold toluene then isolated Pattern C 1:0.5 toluene 1:0.006IPA

Below is a Table which summarises predominantly Pattern C form thermalcharacteristics.

Sample name Exo between 105 and 113^(◦)C Endo at 111.0^(◦)C Endo at111.3^(◦)C Endo at 112.1^(◦)C Endo at 112.4^(◦)C Endo at 113.3^(◦)C Endoat 113.6^(◦)C Endo at 115.0^(◦)C Endo at 115.5^(◦)C Endo at 117.8^(◦)CEndo at 120.2^(◦)C Endo at 122.0^(◦)C Endo at 124^(◦)C 5MeODMT benzoate21-01-060 A1 (air dried 1 hour) P Y Y 5MeODMT benzoate 21-01-060 B1 (airdried 20 hours) Y Y Y Y 5MeODMT benzoate 21-01-064 A Y Y Y Y Y 5MeODMTbenzoate 21-01-064 A (air dried 4 hours) (DSC at 2.5° C.min⁻ ¹) Y Y Y Y5MeODMT benzoate 21-01-064 A (air dried 44 hours) Y Y Y Y 5MeODMTbenzoate 21-01-064 B Y Y Y Y Y Characteristic of Pattern BCharacteristic of Pattern A

5MeODMT benzoate lot 21-01-064 B was produced by reverse anti-solventaddition of an IPA solution to toluene. XRPD revealed Pattern C whichwas supported by a ratio of 1:0.5 of salt to toluene by 1H NMRindicating a toluene hemi-solvate. DSC examination revealed a bimodalendothermic event with peak temperatures of 111.3° C. and 112.1° C.,this indicates the endothermic event at 111° C. in the Pattern Bmixtures was a result of residual Pattern C. There were endothermicevents indicative of Pattern B form, which suggested transformation toPattern B form then Pattern A form.

5MeODMT benzoate lot 21-01-064 A was produced by the same methodology as064 B but was equilibrated for 3 hours before isolation. XRPD and 1H NMRrevealed identical characteristics as 064 B. However, DSC examinationrevealed a different major multi-modal endothermic event with a peaktemperature of 115.0° C.

5MeODMT benzoate lot 21-01-064 A (air dried 44 hours) and 21-01-060 B1air dried (20 hours) were produced similarly to 064 A but air dried forlonger. XRPD revealed a mixture of Pattern C and Pattern B for both, 1HNMR revealed less toluene in 060 B1 than for 064 A, which is believed tobe a result of air drying which supports the presence of Pattern B formin the sample by XRPD. DSC examination revealed an endothermic eventwith a peak temperature of 111.3° C. for both, followed by multipleunique endothermic events.

5MeODMT benzoate lot 21-01-064 A (air dried 4 hours) was produced by airdrying 064 A. XRPD revealed a mixture of Pattern C with some Pattern B.DSC examination revealed a broad exothermic event between 105 and 113°C. followed by a weak endothermic event indicative of Pattern C form andendothermic events indicative of Pattern B form. The change to theheating rate is the cause of the change to thermal behaviour, as the DSCthermograph of 21-01-064 A (44 hour air dried) sample is similar to21-01-064 A the transformation of Pattern C form occurred in situ duringthe examination.

5MeODMT benzoate 21-01-060 A1 (air dried 1 hour) was produced by thesame methodology as 064 A but isolated immediately. XRPD revealed amixture of Pattern C and some Pattern B. DSC examination revealed athermograph indicative of Pattern B form with a minor exothermic eventat ca 109° C.

5MeODMT benzoate Pattern C form is a toluene hemi-solvate it has nocharacteristic endothermic event except for a melt between 110° C. and115° C. The XRPD pattern of the toluene hemi-solvate of 5MeODMT benzoateis distinct to 5MeODMT benzoate. Desolvation may occur under ambientconditions and it is considered that Pattern B form is produced.

The thermal characteristics will be influenced by the loss of tolueneduring DSC examination.

Pattern D

The Table below is a summary of predominantly Pattern D formcompositional and crystallographic characteristics.

Sample name Comments Crystalline character Composition by 1H NMR 5MeODMTbenzoate 21-01-058 D Exposure of amorphous form to anisole vapoursPattern D and A 1:0.47 anisole 5MeODMT benzoate 21-01-064 E Addition ofIPA solution to cold anisole, equilibrated for 3 hours, then isolatedPattern D 1:1.04 anisole 1:0.11 IPA 5MeODMT benzoate 21-01-064 E (airdried 4 hours) Addition of IPA solution to cold anisole, equilibratedfor 3 hours, then isolated and air dried for 4 hours Pattern D 5MeODMTbenzoate 21-01-064 E (air dried 44 hours) Addition of IPA solution tocold anisole, equilibrated for 3 hours, then isolated and air dried for44 hours Pattern D and B 5MeODMT benzoate 21-01-064 F Addition of IPAsolution to cold anisole then isolated Pattern D 1:0.503 anisole 1:0.01IPA

The table below shows a summary of predominantly Pattern D form thermalcharacteristics.

Sample name Endo at 111.2° C. Endo at 117.8° C. Endo at 118.6° C. Endoat 119.2° C. 5MeODMT benzoate 21-01-058 D Y 5MeODMT benzoate 21-01-064 EY 5MeODMT benzoate 21-01-064 E (air dried 4 hours) Y Y 5MeODMT benzoate21-01-064 E (air dried 44 hours) Y Y Y 5MeODMT benzoate 21-01-064 F Y Y

5MeODMT benzoate lot 21-01-064 F was produced by reverse anti-solventaddition of an IPA solution to anisole and isolated immediately. XRPDrevealed a diffraction pattern concordant with Pattern D, which wassupported by a ratio of 1:0.503 for anisole by 1H NMR indicating ahemi-solvate. DSC examination revealed a bimodal endothermic event withpeak temperatures of 118.61° C. and 119.21° C.

5MeODMT benzoate lot 21-01-064 E was produced by reverse anti-solventaddition of an IPA solution to anisole, then equilibrated for 3 hoursbefore isolation. XRPD revealed Pattern D but this was not supported by1H NMR which revealed a ratio of salt to anisole of 1:1.04, the isolatedsolid was damp after isolation. DSC examination revealed very poorlydefined broad endothermic events with peak temperatures of 113.51° C.and 161.93° C., the endothermic event at 113.51° C. is believed to be aresult of the melting of the hemi-solvate present by XRPD followed byevaporation of anisole. The DSC thermograph is not consideredrepresentative of Pattern D form due to the solvent content.

5MeODMT benzoate lot 21-01-058 D was produced by exposure of theamorphous form to anisole vapour. XRPD revealed a mixture of Pattern Dand some Pattern A diffractions which was supported by 1H NMR whichrevealed a ratio of salt to anisole of 1:0.47 indicating an anisolehemi-solvate. DSC examination revealed an endothermic event with a peaktemperature of 118.6° C., which is concordant with the data collectedfrom 064 F. However, the melt of Pattern A form is not revealed in theDSC thermograph, this could be modified by the liberated anisole solventpresent in the sample.

5MeODMT benzoate lot 21-01-064 E (air dried 4 hours) was produced by airdrying 064 E for 4 hours. XRPD revealed Pattern D. DSC examination wasperformed at 2.5° C.min-1 with the aim to resolve the bimodalendothermic event observed in the thermograph of 064 E. DSC examinationrevealed a minor endothermic event with a peak temperature of 111.24°C., this endothermic event is concordant with the broad endothermicevent observed in 064 E. The better resolution of this endothermic isbelieved to be a result of the slower heating rate, or due to removal ofresidual anisole by air drying. This was followed by a major endothermicevent with a peak temperature of 117.90° C. which is concordant with 058D and 064 F.

5MeODMT benzoate lot 21-01-064 E (air dried 44 hours) was produced byair drying 064 E (air dried 4 hours) for a further 40 hours. XRPDrevealed a mixture of Pattern D with some Pattern B diffractions. DSCexamination revealed a thermograph concordant with 064 E (4 hours airdried). The Pattern B form content was not evident in the DSCthermograph this is believed to be caused by the liberated anisolesolvent present in the sample, similar to 058 D.

5MeODMT benzoate Pattern D form is an anisole hemi-solvate and has beenproduced directly from exposure of the amorphous form to anisole vapouras well as reverse anti-solvent addition from an IPA solution to coldanisole. No characteristic thermal behaviour has been identifiedalthough, endothermic events near 118° C. are common and the lack ofrecrystallisation to Pattern B or A forms is believed to be due to thepresence of residual anisole.

Pattern E

The Table below is a summary of predominantly Pattern E formcompositional and crystallographic characteristics.

Sample name Comments Crystalline character Composition by 1H NMR 5MeODMTbenzoate 21-01-064 C Addition of IPA solution to cold chlorobenzene,equilibrated for 3 hours, then isolated Pattern E 1:0.506 chlorobenzene1:0.04 IPA 5MeODMTbenzoate 21-01-064 C (air dried 4 hours) Addition ofIPA solution to cold chlorobenzene, equilibrated for 3 hours, thenisolated and air dried for 4 hours Pattern E 5MeODMT benzoate 21-01-064C (air dried 44 hours) Addition of IPA solution to cold chlorobenzene,equilibrated for 3 hours, then isolated and air dried for 44 hoursPattern E 5MeODMT benzoate 21-01-064 D Addition of IPA solution to coldchlorobenzene then isolated Pattern E 1:0.512 chlorobenzene 1:0.01 IPA

The table below is a summary of predominantly Pattern E form thermalcharacteristics, the endothermic event at 123.7° C. is characteristic ofPattern A.

Sample name Exo between 105 and 115° C. Endo at 110.3° C. Endo at 111.3°C. Endo at 113.1° C. Endo at 114.3° C. Endo at 115.1° C. Endo at 115.8°C. Endo at 119.1° C. Endo at 123.7° C. 5MeODMT benzoate 21-01-064 C Y YY 5MeODMT benzoate 21-01-064 C (air dried 4 hours) Y Y Y 5MeODMTbenzoate 21-01-064 C (air dried 44 hours) Y Y 5MeODMTbenzoate 21-01-064D Y Y Y

5MeODMT benzoate lot 21-01-064 D was produced by reverse anti-solventaddition of an IPA solution to chlorobenzene. XRPD revealed Pattern E,this was supported by 1H NMR which revealed a ratio of salt tochlorobenzene of 1:0.506 indicating a chlorobenzene hemi-solvate. DSCexamination revealed a bimodal endothermic event with peak temperaturesof 111.3° C. and 113.1° C., followed by a minor endothermic event with apeak temperature of 119.1° C.

5MeODMT benzoate lot 21-01-064 C was produced by reverse anti-solventaddition of an IPA solution to cold chlorobenzene, then equilibrated for3 hours before isolation. XRPD revealed Pattern E, this was supported by1H NMR which revealed a ratio of salt to chlorobenzene of 1:0.512indicating a hemi-solvate. DSC examination revealed a trimodalendothermic event with peak temperatures of 111.3° C., 113.1° C., and114.3° C. There are similarities between DSC thermographs of 064 D and Cbut the endothermic event at 119.1° C. is not present in 064 C and 064 Ddid not reveal a trimodal endothermic event. The differences in the DSCthermograph are of note since the XRPD patterns were identical and 1HNMR revealed hemi-solvates.

5MeODMT benzoate lot 21-01-064 C (air dried 4 hours) was produced by airdrying 064 C for 4 hours. XRPD revealed Pattern E. DSC examination wasperformed at 2.5° C.min-1 and revealed a broad exothermic event followedby a minor endothermic event at 114.3° C. but much weaker in comparisonto the same endothermic event in 064 C. This was followed by the majorendothermic event at 123.7° C. which is indicative of Pattern A form.The DSC thermograph is similar to the previous 2.5° C.min-1 DSCexamination and is generating Pattern A form during the DSC examination.

5MeODMT benzoate lot 21-01-064 C (air dried 44 hours) was produced byair drying 064 C (air dried 4 hours) for a further 40 hours. XPRDrevealed Pattern E. DSC examination revealed a bimodal endothermic eventwith peak temperatures of 115.1° C. and 115.8° C. The endothermic eventof 064 C (air dried 44 hours) is similar to 064 C but peaks at aslightly higher temperature.

5MeODMT benzoate Pattern E form is a chlorobenzene hemi-solvate with nodefined thermal characteristics except for a multi-modal endothermicevent between 110 and 117° C. Similarly, to the anisole hemi-solvate,Pattern A and B forms do not recrystallise from the melt. Chlorobenzenehemi-solvate appears to not desolvate when open to ambient conditionsand did not desolvate over 44 hours.

Example 29: Hemi-solvates

Equilibration of suspensions in anti-solvent (toluene, anisole, andchlorobenzene) at -10° C. afforded the expected hemi-solvate by XRPD and1H NMR spectroscopy and TGA.

The partial desolvation of hemi-solvates is considered to affordmulti-modal endothermic events observed in the DSC thermographs, aconsequence of changing composition and the applied heating rate.

Desolvation of hemi-solvates in vacuo at 50° C. for 22 hours affordedPattern B form material by XRPD, DSC, however, some residualhemi-solvate remained in all samples.

The DSC thermograph of the hemi-solvates were similar to those isolatedfrom IPA/antisolvent but with minor differences which are considered tobe a consequence of how they were prepared.

Drying 5MeODMT benzoate toluene hemi-solvate and chlorobenzenehemi-solvate in vacuo at 50° C. for 67 hours afforded Pattern A form,but the anisole hemi-solvate afforded predominantly Pattern B form.

Addition of 5MeODMT benzoate/IPA solution to toluene at -10° C. then airdried for 5 minutes afforded the toluene hemi-solvate when performed ona 1 g input.

Drying 5MeODMT benzoate toluene hemi-solvate at 50° C. for 24 hoursafforded Pattern B form.

5MeODMT benzoate batches 20/53/057-FP and 20/20/123FP demonstratedsimilar particle habits of large hexagonal/rhombus plates (ca. 500 µm to1 mm in length) and some smaller plates that demonstrated accretion onthe plate surfaces and significant evidence of broken fine particles andplates, potentially due to attrition.

This was different to batches 20/20/150FP2 T=0 and 20/20/154FP whichdemonstrated similar particle habits of accreted, jagged clusters ofirregular plates, (ca. 250 to 600 µm in length) and broken, irregularplates and crystallites (some <20 µm in length) that were indicative ofparticle attrition.

The significant difference in particle size and habit between thebatches is believed to have an impact on isolation, flowability andkinetic dissolution rate of the solids, highlighting the importance of acontrolled crystallisation.

Example 30: Patterns F and G

5MeODMT benzoate methyl benzoate hemi-solvate (Pattern F form) has beenisolated from controlled cooling of a clarified 5MeODMT benzoate methylbenzoate solution from 50° C. to -10° C.

5MeODMT benzoate 2-chlorotoluene hemi-solvate (Pattern G form) has beenisolated from controlled cooling of a clarified 5MeODMT benzoate2-chlorotoluene solution from 80° C. to -10° C.

Equilibration in α,α,α-trifluorotoluene did not afford a hemi-solvate asanticipated from a monosubstituted aromatic solvent. Equilibration incumene afforded Pattern B form, which indicated a cumene hemi-solvate.

DVS examination of amorphous 5MeODMT benzoate revealed a weight loss ofca. 2% indicating the elimination of a component and confirming that astable hydrate of 5MeODMT benzoate was not isolated.

Pattern A form is the most stable version of 5MeODMT benzoate and is thethermodynamically favoured product except when isolated from a smallselection of solvents, which afforded the respective hemi-solvate.

Stability studies revealed conversion of all patterns to Pattern A formwhen dried in vacuo at 50° C. However, Pattern B form has been shown tobe stable when open to atmosphere at ca. 20° C. for up to 12 days.Pattern C form underwent partial conversion to Pattern B form within 24hours when open to atmosphere at ca. 20° C., but failed to convert anyfurther from a Pattern B/C mixed version over an additional 11 days.

FTIR spectra for Patterns A, B and C were overall similar though therewere some unique bands in Pattern A form and absent bands that wereotherwise present and shared by Patterns B and C forms.

Controlled Cooling Crystallisation Investigation With an ExpandedSolvent Selection

Initial cooling crystallisation investigation of 5MeODMT benzoaterevealed Pattern A form was isolated from most solvents exceptchlorobenzene which was consistent with Pattern B form. The range ofsolvents was expanded, with an emphasis on esters and aromatics.

5MeODMT benzoate lot 20/20/150FP2, 50 mg ±1mg, was charged tocrystallisation tubes A-L. Minimal solvent at 50° C. was charged toafford a clear solution as detailed in the Table below. Crystallisationtubes I, J, K, and L remained as suspensions at 12.5 mg.ml-1 at 50° C.and so were heated to 80° C. to afford clear solutions.

Solutions were clarified into crystallisation tubes at 50° C. and werecooled to -10° C. at a rate of 10° C.hr-1, then equilibrated at -10° C.for 12 hours, then agitated at -10° C. at 400 rpm for 30 minutes whichafforded a mobile suspension for all samples except Sample I whichremained a solution. Further equilibration with agitation at -10° C. at400 rpm for 3 hours afforded a thin suspension. All samples wereisolated via isolute cartridge and air dried for 5 minutes beforecharacterisation.

Sample F isolated from methyl benzoate was a thick white paste after airdrying for 5 minutes and was left to air dry on the XRPD sample holderfor a further 30 minutes which then afforded a dry powder.

Cryst. tube Solvent Solubilitymg.ml⁻ ¹ at°C Observations A Methylacetate 33.3 at 50 Crystals grew during controlled cooling, thenagitated to form a mobile suspension B n-Propyl acetate 20 at 50 Clearsolution post equilibration that afforded a mobile suspension followingbrief agitation C Iso-Propyl acetate 16.7 at 50 Crystals grew duringcontrolled cooling, then agitated to form a mobile suspension DIso-Butyl acetate 12.5 at 50 Clear solution post equilibration thatafforded a mobile suspension following brief agitation E Ethyl formate40 at 50 Crystals grew during controlled cooling, then agitated to forma mobile suspension F Methyl benzoate 50 at 50 Clear solution postequilibration that afforded a mobile suspension following briefagitation G Methyl propionate 40 at 50 Crystals grew during controlledcooling, then agitated to form a mobile suspension H4-Methyl-2-pentanone 25 at 50 Clear solution post equilibration thatafforded a mobile suspension following brief agitation I Cumene 12.5 at80 Clear solution post equilibration that afforded a mobile suspensionfollowing agitation for 3 hours J Toluene 12.5 at 80 Crystals grewduring controlled cooling, then agitated to form a mobile suspension K2-Chlorotoluene 12.5 at 80 Crystals grew during controlled cooling, thenagitated to form a mobile suspension L α,α,α-Trifluorotoluene 12.5 at 80Crystals grew during controlled cooling, then agitated to form a mobilesuspension

5MeODMT benzoate lots 21-01-073 B, C, D, E, G, H, and L were isolatedfrom n-propyl acetate, isopropyl acetate, iso-butyl acetate, ethylformate, methyl propionate, 4-methyl-2-pentanone, andα,α,α-trifluorotoluene respectively.

The XRPD of these samples revealed powder patterns concordant with5MeODMT benzoate lot 20-37-64, Pattern A.

The DSC thermograph of a selection of pattern A material revealed acommon endothermic event with a peak temperature ranging from 123.07° C.to 124.17° C. with an enthalpy of ca. 140 J.g-1, which is characteristicof Pattern A form. The ¹H NMR spectra of 5MeODMT benzoate lots 21-01-073B, E, H, and L isolated following controlled cooling, then air dried for5 minutes revealed the stoichiometry of the salts to be 1:1 and alsorevealed a salt to solvent ratio ranging from 1:0.0155 to 1:0.027.

5MeODMT benzoate lot 21-01-073 A was isolated from controlled cooling ofa methyl acetate solution from 50° C. to -10° C., then air dried for 5minutes.

The XRPD of 5MeODMT benzoate lot 21-01-073 A revealed the diffractionpattern was concordant with 5MeODMT benzoate lot 20-37-64, Pattern A(FIG. 83 ), but featured diffractions at 21 and 24.6 °2Θ that were moreintense. The difference in intensity was likely a result of preferredorientation.

FIG. 83 shows XRPD pattern comparison of 5MeODMT benzoate lot 21-01-073A, 21-01-049 B1, Pattern B, and 20-37-64, Pattern A.

The DSC thermograph of 5MeODMT benzoate lot 21-01-073 A revealed anendothermic event with a peak temperature of 123.58° C., this ischaracteristic of Pattern A form.

The 1H NMR spectrum of 5MeODMT benzoate lots 21-01-073 A isolatedfollowing controlled cooling, then air dried for 5 minutes revealed thestoichiometry of the salts to be 1:1 and also revealed a salt to solventratio of methyl acetate of 1:0.033. 5MeODMT benzoate lot 21-01-073 F wasisolated from controlled cooling of a methyl benzoate solution from 50°C. to -10° C., then air dried for 5 minutes. After air drying for 5minutes the sample was a paste, air drying further for 30 minutesafforded a damp powder.

The XRPD of 5MeODMT benzoate lot 21-01-073 F revealed an XRPD patternwith an amorphous halo (FIG. 84 ). The sample was re-run after furtherair drying. The XRPD of 5MeODMT benzoate 21-01-073 F (re-run) revealed adiffraction pattern concordant with the initial measurement but with areduced amorphous halo (FIG. 85 ). The diffraction pattern demonstratedsome similarities with both Pattern A and B (FIG. 86 ) but the presenceof unique diffractions and absence of characteristic Pattern A andPattern B diffractions indicate this material to be a unique solid formversion, identified herein as Pattern F form.

FIG. 84 shows XRPD pattern comparison of 5MeODMT benzoate lot 21-01-073F and 21-01-073 F rerun.

FIG. 85 shows XRPD pattern comparison of 5MeODMT benzoate lot 21-01-073F rerun, 21-01-049 B1, Pattern B, and 20-37-64, Pattern A.

FIG. 86 shows XRPD pattern expansion comparison of 5MeODMT benzoate lot21-01-073 F rerun, 21-01-049 B1, Pattern B, and 20-37-64, Pattern A.

The DSC thermograph of 5MeODMT benzoate lot 21-01-073 F (re-run)revealed a broad endothermic event with a peak temperature of 90.50° C.,this was followed by a small endothermic event with a peak temperatureof 106.65° C. This was followed by a broad and shallow endothermic eventwith a peak temperature of 180.35° C.

DSC examination was repeated after the sample was stored in a sealedcontainer for 24 hours. The DSC thermograph revealed a major endothermicevent with a peak temperature of 95.33° C., followed by an exothermicevent with a peak temperature of 102.70° C. This was followed by anendothermic event with a peak temperature of 113.77° C.

The 1H NMR spectrum of 5MeODMT benzoate lots 21-01-073 F isolatedfollowing controlled cooling, then air dried for 5 minutes, revealed thestoichiometry of the salts to be 1:1 and also revealed a salt to solventratio of 1:0.59. After air drying, the paste-like consistency indicatedthe presence of methyl benzoate, the visually damp powder following 30minutes of air drying, indicates that residual methyl benzoate was stillpresent. However, due to the unique diffraction pattern and DSCthermograph, combined with the stoichiometry close to 1:0.5 and thepropensity of the 5MeODMT benzoate salt to form hemi-solvates witharomatic solvents, this sample is believed to be a methyl benzoatehemi-solvate.

5MeODMT benzoate lot 21-01-073 I was isolated from controlled cooling ofa 5MeODMT benzoate cumene solution from 50° C. to -10° C., then airdried for 5 minutes.

The XRPD of 5MeODMT benzoate lot 21-01-073 I revealed the diffractionpattern was concordant with SPS5520 21-01-049 B1, Pattern B.

The DSC thermograph of 5MeODMT benzoate lot 21-01-073 I revealed anendothermic event with a peak temperature of 109.24° C. with a broadshoulder at ca. 100° C. This was followed by an exothermic event with apeak temperature of 111.35° C., then an endothermic event with a peaktemperature of 120.31° C. This was followed by a broad exothermic eventwith a peak temperature of 146.19° C. This thermal profile resemblehistoric Pattern B samples, although the post-final melt exotherm wasknown.

The 1H NMR spectrum of 5MeODMT benzoate lots 21-01-073 I isolatedfollowing controlled cooling, then air dried for 5 minutes revealed thestoichiometry of the salts to be 1:1 and also revealed a salt to solventratio of 1:0.035.

5MeODMT benzoate lot 21-01-073 J was isolated from controlled cooling ofan 5MeODMT benzoate toluene solution from 50° C. to -10° C., then airdried for 5 minutes.

The XRPD of 5MeODMT benzoate lot 21-01-073 J revealed the diffractionpattern was concordant with 5MeODMT benzoate lot 21-01-064 A, Pattern C.

The DSC thermograph of 5MeODMT benzoate lot 21-01-073 J revealed anendothermic event with peak temperatures of 110.00° C., 115.03° C., and120.60° C. The DSC thermograph is similar to 5MeODMT benzoate lot21-01-071 C1, previously isolated Pattern C form material, although theminor peaks are different which is believed to be a consequence ofsample preparation.

The 1H NMR spectrum of 5MeODMT benzoate lots 21-01-073 J isolatedfollowing controlled cooling, then air dried for 5 minutes revealed thestoichiometry of the salts to be 1:1 and also revealed a salt to solventratio of 1:0.473, confirming the isolation of the Pattern C form toluenehemi-solvate.

5MeODMT benzoate lot 21-01-073 K was isolated from controlled cooling ofan 5MeODMT benzoate 2-chlorotoluene solution from 50° C. to -10° C.,then air dried for 5 minutes.

The XRPD of 5MeODMT benzoate lot 21-01-073 K revealed a diffractionpattern that was unique (FIG. 87 ) and is herein identified as PatternG.

FIG. 87 shows XRPD pattern comparison of 5MeODMT benzoate lot 21-01-073K, 21-01-049 B1, Pattern B, and 20-37-64.

The DSC thermograph of 5MeODMT benzoate lot 21-01-073 K revealed anendothermic event with peak temperatures of 111.28° C. and 119.61° C.

The 1H NMR spectrum of 5MeODMT benzoate lots 21-01-073 K isolatedfollowing controlled cooling, then air dried for 5 minutes revealed thestoichiometry of the salts to be 1:1 and also revealed a salt to solventratio of 1:0.516, thus Pattern G form is believed to correspond to a2-Chlorotoluene hemi-solvate.

The Table below is a summary of samples isolated from this controlledcooling experiment and the XRPD patterns afforded.

Sample Solvent XRPD pattern DSC Composition by ¹H NMR A Methyl acetate AN/C 1:0.033 solvent B n-Propyl acetate A A 1:0.027 solvent C Iso-Propylacetate A N/C N/C D Iso-Butyl acetate A N/C N/C E Ethyl formate A A1:0.016 solvent F Methyl benzoate F 95.33° C. 1:0.59 solvent G Methylpropionate A N/C N/C H 4-Methyl-2-pentanone A A 1:0.016 solvent I CumeneB 109.24° C. + 120.31° C. 1:0.035 solvent J Toluene C 120.60° C. 1:0.473solvent K 2-Chlorotoluene G 119.61° C. 1:0.516 solvent Lα,α,α-Trifluorotoluene A A Obscured

Example 31: DVS Examination of Amorphous 5MeODMT Benzoate Produced viaLyophilisation

5MeODMT benzoate 20/20/150FP2, 150 mg, was dissolved in deionised (DI)water, 5ml affording a clear solution. The solution was clarified into a500 ml round bottom flask, the round bottom flask was rotated in anacetone/dry ice bath to freeze the solution in a thin layer around theflask. The ice was sublimed in vacuo at ambient temperature affording afluffy white solid. The solid was removed from the round bottom flaskand transferred to the DVS instrument. During this transfer, the solidcollapsed to a sticky gum.

The sample was examined by DVS from 40% RH and cycled between 0%RH and90%RH twice.

XRPD was collected on a portion of the sample post-lyophoilisation andpost-DVS examination.

The XRPD of 5MeODMT benzoate before DVS analysis revealed an amorphousdiffraction pattern which was expected (FIG. 88 ). FIG. 88 shows XRPD of5MeODMT benzoate lot 21-01-078.

The DVS examination demonstrates an initial weight reduction of ca. 1.4%from the start of the investigation during the first desorption cycle(FIG. 89 ) which was much lower than the 5 wt% required for a 5MeODMTbenzoate monohydrate. Weight reduction continues despite the RHincreasing to 70%RH during the first sorption. At 80 and 90%RH on thefirst sorption cycle, there is a small increase in weight. Followingthis there is a weight reduction to the minimum on the second desorptioncycle, on the subsequent sorption cycle there is no change in weightuntil 5%RH, between 50%RH and 90%RH there is a weight increase of 0.2%.

FIG. 89 shows DVS isothermal plot of 5MeODMT benzoate lot 21-01-078.

The XRPD of 5MeODMT benzoate lot 21-01-078 after DVS examination at90%RH revealed a diffraction pattern concordant with Pattern A (FIG. 90).

FIG. 90 shows XRPD pattern comparison of 5MeODMT benzoate lot 21-01-078(post-DVS) and 20-37-64.

Amorphous 5MeODMT benzoate is unstable and undergoes transformation toPattern A form under all conditions studied. Under ambient conditions itis believed that the amorphous version uptakes moisture from theatmosphere which is eliminated from the sample following conversion toPattern A form. Such a conversion is not considered to be via a hydrateas there has been no observed evidence of a 5MeODMT benzoate hydrate.Alternatively, the process of lyophilisation could seem complete when infact some moisture remains bound to the solid. Upon evacuation of thelyophilisation vessel to atmospheric pressure, the low density,voluminous solid contracts, entrapping the moisture to afford the gumthat is then ejected as the amorphous gum and converts to the morestable, ordered Pattern A form version.

Example 32: FTIR Spectroscopy of 5MeODMT Benzoate Patterns A, B and C

FIG. 91 shows FTIR overlay of 5MeODMT benzoate Pattern A form(20-20-150FP2), Pattern B form (21-01-071 C2) and Pattern C form(21-010071 C1).

FIG. 92 shows FTIR overlay of 5MeODMT benzoate Pattern A form(20-20-150FP2), Pattern B form (21-01-071 C2) and Pattern C form(21-010071 C1) at 450 to 2000 cm-1.

FIG. 93 shows FTIR overlay of 5MeODMT benzoate Pattern A form(20-20-150FP2), Pattern B form (21-01-071 C2) and Pattern C form(21-010071 C1) at 450 to 2000 cm-1; spectra separated.

Inspection of FTIRs reveals the Pattern A form demonstrates a number ofbands of significantly different intensity compared to Patterns B formand C form. Such notable bands were observed at ca. 3130, 1540, 1460,1160 and 690 cm-1, whilst key absent (or significantly reducedintensity) bands present in Patterns B and C included those observed atca. 3230 and 1640 cm-1.

Patterns B and C forms demonstrated far fewer differences in their FTIRsto one another, as when compared to the FTIR of the Pattern A form.

This was anticipated when it is considered that the Pattern C formhemi-solvate desolvates somewhat readily to afford the Pattern B form,resulting in a relatively small change to the crystal lattice comparedto the energy required (i.e.; drying in vacuo at elevated temperature)to induce conversion of Pattern B form to Pattern A form, restructuringthe crystal lattice to a greater extent than facile desolvation.

Example 33: Stability of Patterns B and C

Drying 5MeODMT benzoate Pattern C form in vacuo at 50° C. for 24 hourshistorically often afforded Pattern B form and Pattern B form is knownto transform to Pattern A form at 90° C. as observed by hot stagemicroscopy. The stability of Pattern A form and Pattern B form underboth atmospheric conditions and in vacuo at 50° C. was investigated todetermine the relationship between the forms.

5MeODMT benzoate lot 21-01-071 C1, Pattern C form, and lot 21-01-071 C2,Pattern B form, were charged to XRPD sample holders and sample vials andleft open to the atmosphere for 12 days.

5MeODMT benzoate lot 21-01-071 C1, Pattern C form, was dried in vacuo at50° C. for 5 days.

XRPD was performed regularly. DSC and 1H NMR spectroscopy were performedon samples where significant differences to the diffraction patternswere observed.

The Table below shows a summary of solid form conversion by XRPD duringthe stability tests.

Sample Drying method XRPD pattern throughout drying Day 0 Day 1 Day 2Day 3 Day 4 Day 5 Day 6 Day 8 Day 12 21-01-071 C1, Pattern C Open toatmosphere at 20 ± 2° C. C C+B n/c n/c C+B n/c C+B C+B C+B 21-01-071 C2,Pattern B Open to atmosphere at 20 ± 2° C. B B n/c n/c B n/c B B B21-01-071 C1, Pattern C In vacuo at 50° C. C B B+A A+B n/c A n/c n/c n/c

Example 34: Competitive Equilibration of 5MeODMT Benzoate Pattern A, B,and C Forms in Solvents

The relationship between 5MeODMT benzoate Pattern A, B, and C forms wasinvestigated to determine the thermodynamically stable version andhierarchy. Competitive equilibration was conducted between Pattern A andB forms, and Pattern A and C forms in a variety of solvents includingIPA and toluene. Pattern A form was expected to be the most stable formgiven its melting point of 124° C. and prevalence during mostinvestigations performed.

5MeODMT benzoate 20/20/150FP2, Pattern A form, 15 mg, was charged to allcrystallisation tubes. 5MeODMT benzoate lot 21-01-071 C2, Pattern Bform, 30 mg, was charged to AB crystallisation tubes. 5MeODMT benzoatetoluene hemi-solvate lot 21-01-071 C1, Pattern C form, 30 mg, wascharged to AC crystallisation tubes. Solvent, 0.5 ml, was charged tocrystallisation tubes as detailed in the Table below. Suspensions wereagitated at 100 rpm at 20 ±2° C. for 24 hours. Suspensions were isolatedvia isolute cartridge and air dried for 5 minutes and characterised byXRPD and DSC.

Solid mixture Solvent ID Summary of solid form characterisation XRPD DSCPattern A (15 mg) + Pattern B (30 mg) IPA AB1 Pattern A Endotherm at124° C. Toluene AB2 Pattern C Endotherm at 122° C. iPrOAc AB3 Pattern AEndotherm at ca. 124° C. + minor events MeCN AB4 Pattern A Endotherm at124° C. MEK AB5 Pattern A Endotherm at 124° C. 2-MeTHF AB6 Pattern AEndotherm at 124° C. Pattern A (15 mg) + Pattern B (30 mg) IPA AC1Pattern A Endotherm at 124° C. Toluene AC2 Pattern C Endotherm at 123°C. + minor events iPrOAc AC3 Pattern A Endotherm at 124° C. MeCN AC4Pattern A Endotherm at 124° C. MEK AC5 Defined Pattern A Endotherm at124° C. 2-MeTHF AC6 Pattern A Endotherm at 124° C.

The XRPD of all samples revealed the majority gave Pattern A.

Sample AC5 isolated from MEK revealed an additional diffraction at 8.8°2Θ however this was considered to be caused by the splitting of thediffraction at 9 °2Θ due to better resolution between diffractions ofthis sample.

The DSC thermograph of most Pattern A form samples revealed anendothermic event with peak temperatures ranging from 123.74° C. to124.22° C. which is indicative of Pattern A form.

The DSC thermograph of 5MeODMT benzoate lot 21-01-079 AB3, isolated fromisopropyl acetate, revealed a series of events between 109° C. and 115°C., then a minor endothermic event with a peak temperature of 115.69° C.This was followed by a major endothermic event with a peak temperatureof 123.85° C. indicative of the Pattern A form.

The minor endothermic events are believed to be due to the incompleteconversion of Pattern B form to Pattern A form via equilibration.

The XRPD of 5MeODMT benzoate lot 21-01-079 AB2 and AC2, bothequilibrated in toluene, revealed a diffraction pattern concordant with5MeODMT benzoate lot 21-01-064 A toluene hemi-solvate, Pattern C form.

The DSC thermograph of 5MeODMT benzoate lot 21-01-079 AB2 revealed abimodal endothermic event with peak temperatures of 114.96° C. and121.92° C. The thermal characteristics are similar to previouslyisolated pattern C samples, including 5MeODMT benzoate lot 21-01-073 J.

The DSC thermograph of 5MeODMT benzoate lot 21-01-079 AC2 revealed aminor endothermic event with a peak temperature of 110.11° C., followedby overlapping endothermic and exothermic events between 110.73° C. and113.23° C. This was followed by an endothermic event with a peaktemperature of 122.82° C., this endothermic event is comparable to themelt of Pattern A form when recrystallised from Pattern B form.

Competitive equilibration of both Pattern A/B form mixtures and PatternA/C form mixtures in solvents that were not previously observed toproduce hemi-solvates demonstrated conversion to the Pattern A form. Itis anticipated that all other hemi-solvates will convert to the PatternA form in these solvents.

Competitive equilibration of both Pattern A/B forms and Pattern A/Cforms in toluene demonstrated conversion to the Pattern C form. It isanticipated that equilibration of 5MeODMT benzoate in a solvent(typically an aromatic solvent) that has the propensity to form ahemi-solvate will afford that particular 5MeODMT benzoate hemi-solvateover the otherwise thermodynamically stable Pattern A form solid formversion.

Example 35: Administration of a 5MeODMT Salt

The physical surroundings of the participant/patient/subject are of highimportance in the character of many psychedelic experiences. The spaceshould be private, meaning that there should be no chance of intrusionby others. Ideally, sound from outside (e.g. the hallway, the street,etc.) will be minimal. The dosing sessions should take place in roomsthat feel like a living room or den rather than a clinical setting.Artwork, plants, flowers, soft furniture, soft lighting, and relateddécor should be employed in creating a cozy and relaxing aesthetic.Artwork with any specific religious iconography, ideologicalconnotation, or tendency to evoke negative emotions should be avoided.The dosing room may also provide comfortable furniture for theparticipant and the therapists, who may sit on either side of theparticipant. Participants under the effect of 5MEODMT may exhibitspontaneous movement or slide off of the bed or couch in their proneposition. It is therefore important to make sure no sharp or hardobjects are nearby that the participant may fall on. Additionally,pillows may be useful to physically support participants who are mobileduring the experience. A therapist can provide physical support to theparticipant by placing a pillow between their hands and theparticipant’s body.

Music may accompany the experience, so the dosing room should beequipped with a stereo. The room should shield the participant fromsights and sounds of the world beyond the room, and the participantshould not have any cause for concern of observation or interruption byanyone other than the therapists.

The space may also contain:

-   The tools for safety procedures and medical devices necessary to    respond in the unlikely event of a medical complication. The    participant should be made aware of these procedures and the    equipment, but as much as possible they should be hidden from view.-   A secured and locked space for study materials and documentation in    the session room or nearby.-   An approved safe for storing the 5MEODMT in the session room or    nearby.-   Audio and video-recording equipment: If allowed in the study    protocol the participant will have already consented to being    recorded, and should be made aware of the equipment, but it should    be placed to be as unobtrusive as possible. Participants may request    the cessation of recording at any time.

Physical Space

The space may be large enough to accommodate chairs for two therapists,the stereo equipment and cabinet for storage of the participant’sbelongings and any extra supplies the therapists may need during theday. The space may accommodate a bed or couch on which the participantcan either sit up or lie down with a comfortable surroundings ofpillows. The space may be at least 100² feet or 10² meters so thatparticipants do not feel cramped or too physically close to therapists.Participants should have room to explore a variety of positionsincluding sitting on the floor or stretch their bodies withoutrestriction. A bathroom should be either accessible directly from thesession room or nearby.

Music

5MEODMT sessions may use a pre-set playlist of nature sounds forcreating a calm atmosphere. These nature sounds are considered to be abackground element, helping drown out any noise from outside the room,and keep the participant focused on their experience. Participants arenot instructed to listen to the sounds in any particular way, but may beasked to focus on it as a way of grounding their senses and relaxingbefore or after session.

Medication Discontinuation

Medication discontinuation can be challenging for participants.Participants are to have discontinued all contraindicated medicationsand completed washout periods prior to Prep-1 with the therapist. Thestudy team members, including the therapist, may provide supportivecheck-in calls with the participant prior to this, as-needed during thewashout period, but should not start Prep-1 until washout is completeand the participant confirms intention to continue with the therapy.

Preparatory Sessions

This treatment model includes three, 60-90 minute preparatory sessionswith the therapist. These take place 7 days, 4 days, and 1 day beforethe 5MEODMT session. Preparatory sessions are designed to take place viatelemedicine, but can be in-person if possible.

Preparatory Session 1

The following topics may be covered in the first preparatory session.

Getting to Know the Participant

The therapist will spend some of the preparation session time getting toknow the participant. The therapist may ask open-ended questions about:

-   How they found out about the treatment and what their expectations    are;-   Current life situation with regards to living situation, work,    school, and important relationships;-   Understanding of their own depression;-   Key life events that the participant feels might be of relevance

The therapist should be listening for how the participant talks aboutthemselves and their relationship to their depression, how they relateto the therapist and study environment, and stay attuned to establishinga sense of trust and rapport with the participant. Clinical impressionsof difficulty forming a trusting relationship with the therapist or anyother clinical factors that could interfere with the participants’ability to engage in the treatment should be noted and discussed withthe study team. Although in the preparatory session stage, the therapistmay learn more of the participant that could be reasons for studyexclusion.

Establishing the Role of the Therapist

Therapists in the 5MEODMT-assisted therapy treatment model form arelationship with study participants which becomes part of the containerin which the 5MDE (subjective experience of 5MeODMT) takes place. Thisformation of this relationship is deliberate on the therapists part andcharacterized by the therapist establishing transparency and trust,taking clinical responsibility for the patient’s wellbeing, andrelational and emotional safety for the patient. The therapeuticrelationship is understood as a critical component of the set andsetting for the therapeutic use of the 5MDE. The communication andestablishment of this relationship is both explicit (overt) and implicit(covert) in the therapists behaviors and mannerisms throughout thetreatment.

Explaining the Therapeutic Model With Participant as Active Participantin Their Process

The therapist should explain the therapeutic model used in this researchstudy to the participant in the first preparation session. Theexplanation should include:

-   Practical aspects:    -   How many meetings with the therapist will occur, and for how        long.    -   That the therapy is thought to work by:        -   Creating a safe container for the experience so that the            participant knows what to expect and can fully let go into            their experience,        -   Helping the participant focus on and explore their own            responses to the experience,        -   Facilitating a process of the participant determining for            themselves how they will put their insights into practice in            their life.-   That the therapists role is:    -   Supporting the participant through the session, engaging in a        series of activities to elicit the participant’s unique        experience and insights, fostering the participant’s process of        implementing the resulting changes in their life.    -   That the therapy is:    -   Not a full deep dive into participant’s personal history, not a        place to do specific problem solving or engage in CBT,        Psychodynamic interpretations, get general advice, or receive        other interventions the participant may be familiar with.

Establishing Physical, Emotional, and Psychological/Relational Safety

Beginning in the first preparatory session the therapist establishes theenvironment of physical, emotional, and psychological safety. Thetherapist explains the safety of 5MEODMT and the safety proceduresrelevant to the participants physical health for the session. Withregards to emotional safety the therapist states that all emotionalexperiences are welcomed, that there is no area of experience that theparticipant is not welcome to share. Safety can also be establishedthrough the calm reassuring presence of the therapist, which does notalways require the use of language.

The use of self-disclosure is not prohibited, but should be used verysparingly. A participant may be seeking safety by asking personalquestions of the therapist. If the therapist chooses to disclose, itshould be brief and under the condition the participant share why thispersonal information is important to them.

Psychological/relational safety is established by assuring theparticipant that their wishes will be respected with regards to the useof touch. Also, the participant is to be reassured that if they choosenot to participate in the 5MDE experience they may do so at any point upuntil drug administration and that this will be respected, and that thetherapy sessions will still be available to them if they make thatchoice.

The therapist can use the following techniques to establish safety withthe participant:

-   Ask open-ended questions that invite the expression of doubts,    hesitancies, or concerns:    -   What questions do you have for me?    -   What more would you like to know about 5MeODMT?    -   What would you find helpful in the event ... ?    -   How could I be of assistance to you if you feel ... ?-   Encourage and engage with the full range of participant’s emotions    and experiences without trying to fix or resolve them:    -   Participant expresses skepticism about the 5MEODMT Experience: I        appreciate you sharing that doubt with me. What do you make of        that in light of your presence here at this time?    -   Participant expresses fear about the 5MDE Experience: What more        can you tell me about your fear and how it manifests for you?        How could I be helpful to you as you experience this?    -   Use affirmations to establish an environment of valuing the        participant’s time and effort:    -   I really appreciate the time you are putting into this treatment        and your willingness to participate in research.    -   Your experience is unique to you and I appreciate the        opportunity to see you through this process.

Expected Potential Subjective Drug Effects (Unity, “Feeling Like Dying”,“the Void”,)

It may be helpful to discuss the concept of “non-ordinary state ofconsciousness” with participants. In the past, “altered state ofconsciousness” was often associated with experienced engendered bypsychedelic compounds. However, alterations of consciousness areexperienced on a daily basis, as moods or feelings shift, or when peopleshift from awake alertness to feeling tired and drowsy. “Non-ordinarystate of consciousness” emphasizes the quality of an experience that isnot ordinarily had on a daily occurrence, but can still be within humanexperience.

The therapist may begin this conversation by asking the participantabout their existing knowledge of 5MEODMT effects, and listen forspecific expectation or ideas about it. The therapist is to encourage anattitude of openness toward the experience, encouraging participants toexplore what kinds/ideas they may have and be open to the possibilitythat it will not be possible to imagine what this will be like.Participants may have specific expectations based on the media, priorexperience with 5MEODMT or other psychedelics, or other kinds ofnon-ordinary states of consciousness. It is important for therapists toprovide a balanced description of what the participant may experience.

Different people have different levels of comfort with “not knowing”what something will be like, or what to expect. The therapist mayexplore the participant’s level of comfort with the unknown, theirrelationship to the idea the future not being fully knowable in anysituation, and how they generally relate to this. Among participantswith depression there may be deep fear of the unknown, anticipation ofwhat is expected in the future (more negative experiences), resulting ina feedback loop of feeling fearful and depressed. Therapists shouldelicit and explore this area during preparation.

Common 5MeODMT Experiences: The therapist should also introduce a fewkey terms and commonly reported experiences known to occur under5MEODMT. These include a feeling of unity, a feeling of dying, and afeeling of entering or experiencing a “void” (absence of materialreality). Some participants may have an existing spiritual,philosophical, or religious belief system through which they willinterpret or make meaning of these experiences. Therapists shouldenquire about this and work with the participant’s own explanation andterms, without taking a stance as to whether these are correct orerroneous..

Social Support and Social Media

Participant’s social support may be assessed during preparation sessionsand be determined by the therapist to be adequate to support the patientthrough the process of change, especially in the event of eitherdisappointment or dramatic symptom reduction. In the event theparticipant has a psychotherapist outside of the study the studytherapist may, with the participant’s permission, have a phone call withthe participants therapist to describe the nature of the study andtherapeutic approach and answer any questions the therapist may have.The study therapist may also educate any friends or family members whoare close to the participant and have questions regarding the nature ofthe study, the 5MEODMT experience, and what to expect. The therapistshould discuss social support with the participant including preparingthe participant for the variety of reactions their friends and familymay have.

Therapists may advise participants to take caution around posting abouttheir experience on social media so as not to elicit excessive publiccommentary. Inadequate social support or use of social media in a waythat may be disruptive to the therapeutic process may be discussed andresolved prior to 5MEODMT administration.

Preparatory Session 2

The following topics may be covered in the second preparatory session.

Drug experience preparation: trust, surrender (let go), embrace,transcendence.

There are several key attitudes towards psychedelic experiences that areconsidered to be conducive to a positive and clinically helpfulexperience. The more participants can embody a relaxed stance towardtheir experience the less likely they are to struggle, inadvertentlycreating a loop of stress and distress that heightens attention tonegative aspects and interpretations. The therapist may educate theparticipant on the purpose of deliberately generating an attitude oftrust, surrendering to the experience, and letting go of attempts tocontrol the experience. Therapists may encourage participants to developan attitude of welcoming and embracing all experiences they may have aspart of their 5MEODMT experience. The therapist may suggest to aparticipant that all aspects of the experience (feelings, sensations,and thoughts) can be welcomed. Previous research with psychedelics hasdemonstrated that a capacity to be absorbed by the experience cancontribute to the potency of a mystical experience.

The Drug Administration

The therapist should explain that on the day of the session that amember of the research team will enter the room briefly to administerthe study drug. The therapist should explain the participantpositioning, e.g. they will be in a seated position on the bed or couch,that the research team member will insert the nasal spray device in onenostril, and that they will be asked to allow the therapist to assistthem in lying down on the bed or couch immediately afterward.

Session Procedures Including Boundaries, Use of Touch, Safety, Etc.

The therapist will explain the process of the session. The session iscontained by the timing of the dosing and the physical environment ofthe dosing room. It begins when the participant enters the room andengages with the therapist in the Session Opening. Session Opening is aformal moment in which the participant and therapist sit together in theroom, all preparations having been made, and playlist started. Thetherapist may lead a breathing exercise of the participant’s choice, ifthe participant is open to engaging in one, and ask the participant toreflect on the values they choose in the preparation session, or anyother value or intention that is important to them. Once the participantsignals that they are ready, a member of the research team willadminister the nasal spray to the participant. Trust and safety are notonly communicated verbally, but also this may be nonverbally through howa therapist holds themselves in the presence of the participant. If atherapist is overly anxious, or fearful, this may be felt by theparticipant. It is important that the therapist is centered throughoutthe dosing session, particularly at times when a participant isexpressing intense affect, unusual somatic expressions, or is asking forsupport.

Somatic Changes and Shifts in One’s Sense of Their Body

Some participants may experience an intensified awareness of their bodysuch as feeling their heart rate more strongly or physical sensations intheir temple. Other participants may be aware of a tingling in theirbody, changes or perceived difficulty breathing, or other unusualphysiological experiences. It is important for the therapist tocommunicate that these changes in perception are normal and should notbe a focus of preoccupation or fear. If these sensations arise, theparticipant should be encouraged to communicate these to the therapist,if they so desire. The therapist should reassure the participant thatthese sensations are expected and are normal to have. The therapist caninform and remind the participant that naturally occurring 5MEODMT hasbeen consumed in other settings for hundreds of years with no indicationthat it is physically harmful, and that these changes are expected andwill resolve shortly.

Discussing Expectations and Intentions

Expectations can be defined as mental representations and beliefs of howsomething in the future will be. Sometimes expectations can beexplicitly identified, and sometimes they are subperceptual, taken forgranted. Both kinds of expectations may be important to treatment. Thetherapist should ask about explicit expectations and encourage theparticipant to acknowledge and set these aside such that they do notengage in comparing their experience to expectations. The therapist isalso listening for subperceptual expectations that may come intoawareness through the therapy. Intentions are ways of relating to abehavior or experience. In the 5MEODMT treatment, it can be importantfor the therapist to elicit and understand the participant’s intentionsas these can vary greatly and may be taken for granted. Therapists areto engage participants in a process of identifying and setting theirintentions such that these are explicit and can be referenced later inintegration. The purpose of the intention is for it to be identified andthen let go of, with the knowledge that it can be part of the 5MED.

Recurrence of Acute Effects

Some individuals who used 5MEODMT in non-clinical contexts have reportedre-experiencing 5MEODMT’s subjective effects in the days after. The doseused, purity, and other factors were not monitored in these cases. Thelikelihood of these reactivations occurring in a controlled clinicalstudy context is not known, but estimated to be less likely.Nonetheless, it is important for participants to be made aware of thisphenomenon. The experience of reactivations are often reported aspleasant, brief (lasting a few moments to minutes), and do not occurwith enough frequency to interfere with a person’s life. Thesereactivations are thought by some as part of the integration process. Ifa participant notices certain activities trigger reactivations, such ascertain meditative states, stimulants, or other drugs, and theparticipant finds these reactivations unpleasant, it should be suggestedto the participant that they avoid such triggers. Processing the 5MEODMTexperience in therapy, as part of integration, may also be helpful.

Discussing the Use of Touch

Therapists in this modality may engage in two types of touch:therapeutic touch, and touch for safety reasons. During preparation thetherapist should explain and define each. Therapeutic touch is touchthat is intended to connect with, sooth, or otherwise communicate withthe participant for therapeutic aims. It is always fully consensual,non-sexual, and the participant is encouraged to decline or ceasetherapeutic touch at any time. Touch for safety reasons can includesupporting a participant who is having trouble walking by offering anarm to hold, or blocking a patient back from leaving the room whileunder acute drug effects. This touch is agreed to in advance, is alwaysnon-sexual, and limited to specific safety concerns. Therapists shoulddiscuss both of these and establish boundaries with participants aheadof session.

Preparing for After the Session (What to Expect, What to Do, SettingAside Time for Integration)

Participants should be encouraged to take some time to rest andintegrate their experience after their session day. Study therapistsshould ask participants to plan for time off after their session, atleast the full day of the session and the day after the session.Therapists should explain that after the acute effects of the 5MeODMThave worn off they will stay together in the room for a while. Thisperiod of time will be for the participant to readjust to theirexperience after the acute effects. They will be asked to share whatthey can recall about their experience and any reactions they have. Theywill not be asked to share anything they don’t want to share, and arewelcome to keep their experience private. They may choose to write ordraw about their experience, art supplies and writing supplies will beavailable. They may be encouraged to spend some time continue to staywith their experience, with the therapist’s support, for around an hour.They will then meet with the study team for a safety assessment beforegoing home. Once at home they are encouraged to rest and continue tostay with the experience and the insights, ideas, or new understandingthey may have from it. Participants should be reminded that they do notneed to share their experience with others unless they want to, and areencouraged to continue to focus on it in whatever way they find mosthelpful. Participants should refrain from returning to work, fromdriving, drinking alcohol, drug use, or being a sole caregiver for achild or dependent for the rest of the day.

Therapist Teaches Breathing Exercise for Dosing Session

When stressed, breaths become shorter and shallower, and when relaxed,the breath becomes longer and slower. Working with the breath is a wayof modulating and regulating one’s mental state. The therapist may teachand practice two breathing techniques with the participant. These aredesigned to help the participant relax their body and mind, toleratestressful or uncomfortable experiences, and develop autonomy throughpractice on their own. These are not for use during the acute effects of5MeODMT, but can be used prior to dosing and afterward.

When teaching the practices, the therapist elicits the participant’sindividual response to each practice to assess suitability of using it.Breathing practices include: Balancing Breath, Diaphragmatic Breath andCounted Breath.

Preparatory Session 3 Values Card Sort With Prompts

The therapeutic protocol may use a customized Personal Values Card Sortto assist with the therapeutic focus on shift in sense of self. This isdone by asking about how people relate to their chosen values before thesession, and how they relate to them afterward, drawing attention toshifts, changes, and using these as a guide for the kind of changes theparticipant may desire to make. It is used as a way to elicitconversation about the participant’s sense of self, beliefs about self,and changes in those senses/beliefs throughout the therapy. Therapistsmay engage participants in the card sort exercise in the thirdpreparation session such that it occurs 1-2 days before the dosingsession.

The Values Card Sort Instructions Are:

-   1. Place five anchor cards in order from 1-5 in front of the    participant from left to right in order of least to most important.-   2. Shuffle the 100 value cards; keep the 2 blank cards separate.-   3. Instruct the participant to sort the cards using the following    script: “I placed five title cards in front of you-not important to    me, somewhat important to me, important to me, very important to me,    most important to me. I’m going to give you a stack of 100 personal    value cards. I would like you to look at each card and place it    under one of the five title cards. There are also two blank cards.    If there is a value you would like to include, write it on the card    and put it in whichever pile you would like. I would like you to    sort all 100 cards, but whether you use the two additional cards is    optional. Do you have any questions?”-   4. When the participant is finished sorting, thank them and invite    them to look at the “most important” category, removing the other    cards from the table.-   5. Read the following: “For the second task, I’d like you to focus    on the top values you put in the “most important” category and    choose the top five.”-   6. When the participant has chosen their top five cards, thank them    read the following: “For the third task, I’d like you to focus on    the top five values you chose and rank them in order from most to    least important.”-   7. When the participant indicates they are finished ordering, check    to make sure you understand how the cards were sorted (ascending or    descending). Point to the #1 spot and say, “I want to make sure I    have this right–is this your number one value?”-   8. Record values on a scoring sheet, journal or by taking a picture    of the cards. Participants should keep a record of their card    selections as well.

Debriefing and Discussion:

Next, invite the participant to engage in a structured discussion ofeach value using a few of the following open-ended prompts, or similarprompts depending on the context of your work:

-   You selected ______ as your #__ value?;-   Please tell me more about what means to you?-   What are some ways has been represented in your life?-   What are some ways you’d like to see more of _ in your life?-   How does your decision to or not relate to this value?-   How much would you like to have in your life?-   How would you know if was increasing or decreasing in your life?-   How does relate to the change you are trying to make (or considering    making)?

Invite the participant to journal about their answers to the samequestions with the remaining cards afterwards. In later sessions it canbe helpful to check in on the values and revisit these questions, seehow answers have changed, and how participants are currently relating totheir values.

Assistant Therapist

The session may be conducted by the therapist with an assistanttherapist such that a second person is available to assist in case ofany adverse event or physical complication in the participants safety.The assistant who will be present for the session should be introducedin Prep Session 3 and included in a conversation such that they get toknow the participant.

Session-Specific Therapeutic Tasks

Therapists should aim to complete the therapeutic tasks outlined aboveaccording to the chart below, while acknowledging that some variationwill occur based on individual participant needs.

Prep Session 1 - Getting to know the participant - Establishing the roleof the therapist - Explaining the therapeutic approach/model withparticipant as active participant in their process - Establishingphysical, emotional, and psychological/relational safety. - Expectedpotential subjective drug effects (unity, “feeling like dying”, “thevoid”,) - Social Support and Social Media Prep Session 2 - Drug specificpreparation: trust, surrender (let go), embrace, transcendence, - DrugAdministration - Session procedures including boundaries, use of touch,safety, etc. - Discussing expectations and intentions - Discussing theuse of touch - Preparing for after the session (what to expect, what todo, setting aside time for integration) - Teach and practice BreathingExercises Prep Session 3 - Values card sort with prompts - Instructionto continue values card sort inquiry for homework after session ifneeded. - Confirm plans for session and review any questions participanthas. - Assistant Therapist joins the session for an introduction ifneeded

5MeODMT Experience Session

The therapist is present with the participant during the session —including pre-experience and post-experience times. This is the onlysession that must be conducted in-person. The site and therapist shouldschedule about 3 hours for the session, including pre-experience andpost-experience time. This does not include the time allotted to engagein baseline measures and enrolment confirmation prior to the session.Local regulatory approvals will determine the minimum length of time aparticipant must be under observation following 5MEODMT administration.

Pre-experience (Around 30 Minutes)

After the participant has completed all enrolment confirmation andrandomization procedures and is cleared to participate, the Therapist,Assistant Therapist, and participant together in the room review allaspects of the room and safety procedures. The therapist shouldintroduce the participant to the team member administering the 5MEODMT,to create a sense of familiarity. Therapist introduces any AssistantTherapist and reviews safety features of the room and the equipmentpresent. Participant has time to ask any questions. The therapist willask about any responses to the situation and how the participant isfeeling about their session. The participant should not be rushed intothe dosing by the therapists. The therapist will ask the participant toengage in a period of relaxation prior to dosing. Participant will beasked to lie down, close their eyes, listen to the music, and, ifwilling, engage in at least one of the breathing exercises with thetherapist’s guidance. When the participant is settled and comfortable,the therapist will initiate the Session Opening. This practice helpscontain and emphasize the specialness of the experience. Therapists willcontact the member of the research team to come to the room andadminister the 5MEODMT. The team member should be aware not to disruptthe peaceful atmosphere of the room. The participant should be in aseated position when insufflating the 5MEODMT, as the effects may befelt quickly, the participant should be transitioned to a prone positionand remain prone for the duration of the effect of the 5MEODMT.

Experience (Around 60 Minutes)

It is expected that the onset of acute effects will occur very rapidlyafter administration. Therapists should be aware of the time ofadministration so they can be aware of the participant’s response inrelation to the expected course of duration. Some participants may wantto know how long they experienced the effects of the 5MEODMT and it isappropriate to share this information if asked. A significant portion ofthe time the participant may be nonverbal, focused inward, and engagingin their experience. It is important for the therapist to be mindfullyaware of the participant, but not interfering with the participant’sexperience, unless it is clear that participant is seeking thetherapist’s support. Therapists are encouraged to engage inself-regulation techniques while the participant is undergoing theirexperience. This may be in the form of slow intentional inhaling andexhaling, or any other activity that helps the therapist ground andself-regulate. This is both for the therapist’s benefit, as well as theparticipants’, because a participant in a heightened non-ordinary statemay be particularly attune to or pick up on their therapist’s anxiety.It is optimal for the therapist to follow the participant’s lead whenchoosing to verbally engage as the 5MEODMT experience appears to besubsiding. Therapists may be eager to ask the participant about theirexperience, but it is preferable to wait until the participant is readyto share on their own. A participant may wish to remain in a period ofsilence, even after the apparent acute 5MEODMT effect is gone. It isappropriate for therapists to greet participants with a friendly smileand welcoming nonverbal behavior, and allow participants to take thelead on sharing when they feel ready.

Post-Experience (around 90 Minutes)

Therapist will encourage the participant to stay with their experiencefor a period of time of at least one hour after the acute effects of the5MEODMT have worn off and the participant is once again aware of theirsurroundings and situation in the treatment room. To stay with theexperience means to continue directing attention toward it in whateverway feels most appropriate to the participant, without turning toengagement in distractions, entertainment, or the concerns of dailylife. During this time the therapist will invite the participant todescribe their experience, if they choose to, and respect the choice notto if the participant is unready. If the participant does describe theirexperience the therapist is to listen and encourage the participant toexpress whatever they would like to share without interpretation orattempts to make meaning. The therapist practices simply listening,encouraging the participant to describe what they can about theexperience. The therapist also offers the participant the option ofresting and listening to the music, or to write about or draw anyaspects of the experience they desire. At the end of this time period,the therapist will verify with the participant that they feel ready toclose the session, will engage in the Session Closing, and contact thestudy team for exit assessment.

Integration Sessions

The key principle of integration sessions is to help the participantfocus on shifts in their perception of themselves and the implicationsof these as they relate to their depression. Self, for the purpose ofthis study, is broadly defined as the narrative or historical self, thesense of a coherent “I” that moves through experiences, and theself-identities one may use. It is key to remember that the sense ofself, or the “I,” is reflected in both the experiencer’s self-experienceand experience of the object of experience, therefore descriptions may,on the surface, be of changes in the perception of the external world,but reflect shifts in the internal processes. To this end, the followingtherapeutic tasks will guide the integration sessions.

These sessions are less structured than preparatory sessions toaccommodate variations in participant responses. There are three tasks:The first should occur at all sessions, the second and third may beintroduced and engaged in if and when the participant is ready andwilling. The tasks are:

Listening and Hearing About the Participant’s Experience

Therapists ask open-ended questions about the participant’s experienceand listen with non-judgmental curiosity to the participant’sdescriptions. Therapists ask only that participants focus on the 5MDEand related material, such that their time together is focused on thetreatment. Therapists should focus inquiry on the participant’sexperience, asking them to tune into any aspect of the three types ofsense of self they can identify.

Reintroducing the Values and Discussing Relationship to Each

The therapist will reintroduce the values identified in the Values CardSort from preparation and bring discussion back to them if and whenappropriate in the integration sessions. There is by no means arequirement to engage in the structured discussion of the values, but itserves as a framework where needed to direct the focus of sessionstoward participants’ shift in sense of self.

The Therapist May Ask for Example, to Reintroduce the Values:

Therapist: Before your 5MDE we discussed a list of Values you hold andhow you were relating to each of those. I’d like to draw our attentionback to that and ask for a little detail about how those ways ofrelating might have shifted. For instance you named “Family” as onething that was important to you, but you were concerned that you weren’tfeeling well enough to be present for family relationships. You said youwere isolating from your family a lot by working on your computer fromyour makeshift office in the garage every evening. How do you relate tothe value of “Family” now?

In the dialogue, the therapist can for example continue to focus onshifts in how the participant is relating to his value of “Family” byenquiring about what he is noticing in this area.

Create ways the participant can act to enhance their relationship totheir chosen values; identify value-oriented action in their life as anintegration practice. Integration can be understood as a process ofembodying or living out the insights one has. In at least one of theintegration sessions, the earliest the therapist feels the participantcan engage in this stage, the therapist should introduce the idea ofidentifying value-oriented actions they can take in their lives asintegration practices. Explaining the concept as above, the therapistcan invite the participant to recall the values they identified (or anyother that is important to them), recall the insights or experiences oftheir 5MEODMT session, and think creatively about things they might tryintentionally doing differently in order to implement positive change intheir relationship to the values based on those insights and experiences

Items: 1. A method of administering 5MeODMT or a pharmaceuticallyacceptable salt thereof to a patient who is diagnosed with depression,the method comprising:

-   the discontinuation of the use by the patient of any mood-altering    substance or any other substance, medications or preparation which    may affect serotonergic function;-   the relaxation of the patient, such as the patient is instructed to    lay down, close their eyes, and listen to music and/or engage in one    or more breathing exercises guided by a therapist;-   optionally, the clearing of their nasal passages, by blowing their    nose, by the patient e.g. whilst sat down;-   the administration of 5MeODMT, optionally by via insufflation, and    optionally wherein the patient is in a prone position for the    duration of the effects of 5MeODMT.

2. The method of item 1, wherein the patient has discontinued the use ofmonoamine oxidase (MAO) inhibitors, CYP2D6 inhibitors, selectiveserotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptakeinhibitors (SNRIs), tricyclic antidepressants (TCAs), lithium,antipsychotics, triptans, tramadol, 5-hydroxytryptophan, herbalpreparations which may contain 5-HTP, St John’s Wort and anybenzodiazepines prior to administration of 5MeODMT.

3. The method of item 1 or item 2, wherein the 5MeODMT is administeredvia the Aptar Unidose (UDS) liquid delivery system.

4. The method of item 1, item 2 or item 3, wherein the 5MeODMT is thebenzoate salt, optionally a polymorph of the benzoate salt.

5. The method of any one of items 1 to 4, wherein the patientparticipates in at least one psychological support session beforeadministration of the 5MeODMT.

6. The method of item 5, wherein the patient participates in at leastthree psychological support sessions before administration of the5MeODMT.

7. The method of item 6, wherein the patient participates in threepsychological support sessions, wherein these sessions take place 7days, 4 days and 1 day before the administration of the 5MeODMT.

8. The method of any one of items 5 to 7, wherein the psychologicalsupport sessions are 60-90 minutes in length.

9. The method of any one of items 5 to 8, wherein at least onetherapeutic intention is discussed during the psychological supportsession.

10. The method of any one of items 5 to 9, wherein self-directed inquiryand experiential processing are practiced during the psychologicalsupport session.

11. The method of any one of items 1 to 10, wherein the patientparticipates in at least one psychological support session afteradministration of the 5MeODMT.

12. The method of item 11, wherein the patient participates in at leastthree psychological support sessions after administration of the5MeODMT.

13. The method of item 11 or item 12, wherein the patient participatesin three psychological support sessions, wherein these sessions takeplace 1 day, 4 days and 7 days after the administration of the 5MeODMT.

14. The method of any one of items 11 to 13, wherein the psychologicalsupport sessions are 60-90 minutes in length.

15. The method of any one of items 1 to 14, wherein the 5MeODMT isadministered to the patient in a room with a substantially non-clinicalappearance.

16. The method of item 15, wherein the room comprises soft furniture.

17. The method of item 15 or 16, wherein the room is decorated usingmuted colours.

18. The method of any one of items 15 to 17, wherein the room comprisesa high-resolution sound system.

19. The method of any one of items 15 to 18 wherein the room comprisesfood and drink for the patient and therapist.

20. The method of any one of items 15 to 19 wherein the room comprisesan approved safe for storing 5MeODMT.

21. The method of any one of items 15 to 20 wherein the room isinsulated such that the patient is shielded from sights and sounds ofthe world beyond the room.

22. The method of any one of items 15 to 21 wherein the room does notcontain any artwork or decoration with any specific religiousiconography, ideological connotation, or other such artwork ordecoration which may evoke negative emotions in a patient.

23. The method of any one of items 15 to 22, wherein the room comprisesa bed or a couch.

24. The method of item 23, wherein the patient lies in the bed or on thecouch for approximately 0.5-8 hours, or a substantial fraction thereof,after administration of the 5MeODMT.

25. The method of any one of items 1 to 24, wherein the patient listensto music for approximately 0.5-8 hours, or a substantial fractionthereof, after administration of the 5MeODMT.

26. The method of any one of items 1 to 25, wherein the patient wears aneye mask for approximately 0.5-8 hours, or a substantial fractionthereof, after administration of the 5MeODMT.

27. The method of any one of items 1 to 26, wherein a therapist providespsychological support to the patient for approximately 0.5-8 hours afteradministration of the 5MeODMT

28. The method of any one of items 1 to 27, wherein the therapist usesguided imagery and/or breathing exercises to calm the patient and/orfocus the patient’s attention.

29. The method of any one of items 1 to28, wherein the therapistprovides reassuring physical contact with the patient.

30. The method of item 29, wherein the therapist holds the hand, arm, orshoulder of the patient.

31. The method of any one of items 1 to 30, wherein the therapistencourages the patient to perform self-directed inquiry and experientialprocessing.

32. The method of item 31, wherein the therapist reminds the patient ofat least one therapeutic intention.

33. The method of any one of items 1 to 32, wherein the therapistcounsels the patient to do one or more of the following:

-   (1) to accept feelings of anxiety,-   (2) to allow the experience to unfold naturally,-   (3) to avoid psychologically resisting the experience,-   (4) to relax, and/or-   (5) to explore the patient’s own mental space.

34. The method of any one of items 1 to 33, wherein the therapist doesnot initiate conversation with the patient.

35. The method of item 34, wherein the therapist responds to the patientif the patient initiates conversation.

36. The method of any one of items 5 to 35, wherein psychologicalsupport is provided remotely to the patient.

37. The method of item 36, wherein the psychological support is providedvia a digital or electronic system.

38. The method of item 37, wherein the digital or electronic system is amobile phone app.

39. The method of item 38, wherein the digital or electronic system is awebsite.

Example 36: Mouse Forced Swim Test

This study aimed to assess the effect of 5MeODMT Benzoate at three dosesin the mouse Forced Swim Test (FST). The forced swim test is a model ofbehavioural despair and is sensitive to detection of various classes ofantidepressant drugs.

Husbandry Housing and Acclimation

Animals received a 72-hour period of acclimation to the test facilityprior to the commencement of testing. Animals were housed four per cagein polycarbonate cages bedded with ¼” bed-o′cob. Cages were changed, andenrichment provided according to standard operating procedures. Animalswere maintained on a 12-hour light/12-hour dark cycle with allexperimental activity occurring during the animals’ light cycle. Allanimal use procedures were performed in accordance with the principlesof the Canadian Council on Animal Care (CCAC).

Food and Water

Certified Rodent Diet (LabDiet® 5001) was offered ad libitum. Animalswere not fasted prior to, or after the experiment was initiated. Waterwas provided ad libitum in glass bottles with stainless steel sippers.

Study Design Test Subjects

Male CD-1 mice from Charles River Laboratories (St. Constant, Quebec,Canada) served as test subjects in this study. Animals generally weighed25-30 g at the time of testing.

Schedule of Events Study Day Key Event Procedure -8 Animal arrivalAcclimation to the animal facility -7, to -1 Daily obs. Daily healthobservations 0 Forced Swim Test Body weights and observations Dosingwith 5-MeO DMT Benzoate, Imipramine, and vehicle Pre-FST behaviouraltest Forced swim test

Treatment Groups

Animals were randomly allocated into the following treatment groups:

Group Treatment Route Pre-treatment time Group Size A Vehicle SC 3 hr N=8 B 5-MeO DMT Benzoate (0.5 mg/kg) SC 3 hr N= 8 C 5-MeO DMT Benzoate(1.5 mg/kg) SC 3 hr N= 8 D 5-MeO DMT Benzoate (5 mg/kg) SC 3 hr N= 8 EImipramine (30 mg/kg) IP 3 hr N= 8

Pre-FST Behavioural Test

On day 0, in addition to the forced swim test animals were evaluated forsigns of 5-HT (serotonin) syndrome. Animals were exposed to activitychambers for 10 minutes at two timepoints post dose: (1) 5-15 minutespost dose, and (2) 2.5 hours post dose.

Forced Swim Test

Male CD-1 mice received the appropriate dose of vehicle, test article,or positive control (treatments summarized above). Following theappropriate pre-treatment time, animals were gently placed into tallglass cylinders filled with water (20-25° C.). After a period ofvigorous activity, each mouse adopted a characteristic immobile posturewhich is readily identifiable. The swim test involves scoring theduration of immobility. Over a 6-minute test session, the latency tofirst immobility is recorded (in seconds). The duration of immobility(in seconds) during the last 4 minutes of the test is also measured.Activity or inactivity from 0-2 minutes is not recorded.

Test Articles 5-MeODMT Benzoate

-   BEW: 1.59 (Benzoate salt form)-   MW: 340.40 g/mol-   Doses: 0.5, 1.5, 5 mg/kg (doses corrected to base)-   Route of administration, dose volume: SC., 10 mL/kg-   Pre-treatment time: 3 hr-   Vehicle: 0.9% Saline

Imipramine

-   BEW: 1.13-   MW: 280.415 g/mol-   Doses: 30 mg/ kg (doses corrected to base)-   Route of administration, dose volume: IP., 10 mL/kg-   Pre-treatment time: 3 hr-   Vehicle: 0.9% Saline

Results

At 3-hour post-dose, over the 6-minute test session, there is a positivetrend in reducing the duration of immobility and increasing latency toimmobility by the low doses of 5MeODMT benzoate (0.5 and 1.5 mg/kg),compared to vehicle-treated mice (time immobile 2-6 minutes, vehicle:190.4 ± 7.7 seconds - 5MeODMT benzoate: 133.2 ± 24.9 seconds (0.5mg/kg), 137.6 ± 17.0 seconds (1.5 mg/kg), 156.8 ± 18.7 seconds (5mg/kg) - Imipramine 46.8 ± 16.6 seconds, FIG. 94 . Latency toimmobility, vehicle: 95.5 ± 4.6 seconds - 5MeODMT benzoate 121.8 ± 22.0seconds (0.5 mg/kg), 120.9 ± 13.3 seconds (1.5 mg/kg), 85.0 ± 9.5seconds (5 mg/kg), imipramine 268.6 ± 30.3 second, FIG. 95 ).

Example 37: Study 5MEO-TOX-PK-DOG

The objective of this toxicokinetic study was to assess and compare thetoxicokinetic profile of the test items, 5MeODMT-HCI (in a vehicle of0.1% metolose, Group 2) and 5MeODMT-benzoate (in a vehicle of 0.2%metolose + 0.01% BZK, Group 4).

On day 1, the vehicle or active test item formulations were administeredto male Beagle dogs intranasally, at a dose level of 0.4 mg/kg in theactive groups (corresponding to freebase). Following administration, aseries of blood samples was collected from each dog at the followingtime points: pre-dose (0), 2, 5, 8, 10, 15, 30 and 60 minutes, and 2-and 8-hours post-dose. Plasma samples were analysed for quantificationof concentration of 5MeODMT in each sample using a validated method.

5MeODMT was not detected in any of the samples collected from thecontrol animals on Day 1 (not shown). Peak plasma exposure levels(C_(max)) were reported at 16.4 ng/mL and 35.4 ng/mL, for Groups 2 and4, respectively (see table below). FIG. 96 presents the time-course plotof mean plasma concentrations, which shows a broadly comparable TKprofile between the HCI and benzoate salt formulations.

Mean C_(max) values for 5MeODMT in groups 2 and 4 on day 1 GroupDesignation Day Dose Level (mg/kg) C_(max) (ng/ml) Mean SE N Group 25MeODMT- HCl + 0.1%Metolose 1 0.4 16.4 1.37 3 Group 4 5MeODMT benzoate +0.2% Metolose + 0.01% BZK 1 0.4 35.4 16.6 3

See also FIG. 96 which shows 5MeODMT Group Mean Plasma Concentration(ng/mL) in Male Beagle Dogs -Group 2 (the 5MEODMT HCI salt formulation)and Group 4 (the 5MEODMT benzoate salt formulation) — Dose Level (0.4mg/kg); wherein the Mean Plasma Concentration of Groups 2 and 4 aresubstantially the same with dose time.

Example 38: Further Embodiments

In one embodiment, there is provided a polymorph of 5MeODMT benzoate ascharacterised by an XRPD pattern as substantially illustrated in any oneof the Figures or as previously or subsequently described.

In one embodiment, there is provided a polymorph of 5MeODMT benzoate ascharacterised by one or more peaks in an XRPD diffractogram assubstantially illustrated in any one of the Figures or as previously orsubsequently described.

In one embodiment, there is provided a polymorph of 5MeODMT benzoate ascharacterised by one or more endothermic events in a DSC thermograph assubstantially illustrated in any one of the Figures or as previously orsubsequently described.

In one embodiment, there is provided a polymorph of 5MeODMT benzoate ascharacterised by TGA thermograph as substantially illustrated in any oneof the Figures or as previously or subsequently described.

In one embodiment, there is provided a polymorph of 5MeODMT benzoate ascharacterised by a DVS isotherm profile as substantially illustrated inany one of the Figures or as previously or subsequently described.

In one embodiment, there is provided a polymorph of 5MeODMT benzoate ascharacterised by a crystalline appearance as substantially illustratedin any one of the Figures or as previously or subsequently described.

In one embodiment, there is provided a polymorph of 5MeODMT benzoate ascharacterised by a particle size distribution as substantiallyillustrated in any one of the Figures or as previously or subsequentlydescribed.

In one embodiment, there is provided a polymorph of 5MeODMT benzoate ascharacterised by a FITR spectra as substantially illustrated in any oneof the Figures or as previously or subsequently described.

In one embodiment, there is provided a polymorph of 5MeODMT benzoateproduced as previously or subsequently described. In one embodiment,there is provided a method of producing a polymorph of 5MeODMT benzoateas previously or subsequently described.

In one embodiment, there is provided a composition comprising apolymorph of 5MeODMT benzoate as previously or subsequently described.

In one embodiment, there is provided a 5MeODMT benzoate solvate ascharacterised as substantially illustrated in any one of the Figures oras previously or subsequently described.

In one embodiment, there is provided a 5MeODMT benzoate hemi-solvate ascharacterised as substantially illustrated in any one of the Figures oras previously or subsequently described.

In one embodiment, there is provided the use of any previously orsubsequently described form of 5MeODMT benzoate in any previously orsubsequently described method of treatment.

Herein disclosed is the use of a composition as herein described for themanufacture of a medicament for the treatment of any one of: conditionscaused by dysfunctions of the central nervous system, conditions causedby dysfunctions of the peripheral nervous system, conditions benefitingfrom sleep regulation (such as insomnia), conditions benefiting fromanalgesics (such as chronic pain), migraines, trigeminal autonomiccephalgias (such as short-lasting unilateral neuralgiform headache withconjunctival injection and tearing (SUNCT), and short-lastingneuralgiform headaches with cranial autonomic symptoms (SUNA)),conditions benefiting from neurogenesis (such as stroke, traumatic braininjury, Parkinson’s dementia), conditions benefiting fromanti-inflammatory treatment, depression, treatment resistant depression,anxiety, substance use disorder, addictive disorder, gambling disorder,eating disorders, obsessive-compulsive disorders, or body dysmorphicdisorders.

Herein disclosed is a method of treating any one of: conditions causedby dysfunctions of the central nervous system, conditions caused bydysfunctions of the peripheral nervous system, conditions benefitingfrom sleep regulation (such as insomnia), conditions benefiting fromanalgesics (such as chronic pain), migraines, trigeminal autonomiccephalgias (such as short-lasting unilateral neuralgiform headache withconjunctival injection and tearing (SUNCT), and short-lastingneuralgiform headaches with cranial autonomic symptoms (SUNA)),conditions benefiting from neurogenesis (such as stroke, traumatic braininjury, Parkinson’s dementia), conditions benefiting fromanti-inflammatory treatment, depression, treatment resistant depression,anxiety, substance use disorder, addictive disorder, gambling disorder,eating disorders, obsessive-compulsive disorders, or body dysmorphic ina patient by the administration of a composition as described herein.

1-80. (canceled)
 81. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT)benzoate.
 82. The 5-MeO-DMT benzoate of claim 81 in crystalline form.83. The 5-MeO-DMT benzoate of claim 82, wherein the crystalline form isPattern B.
 84. The 5-MeO-DMT benzoate of claim 83, wherein thecrystalline form Pattern B is characterised by one or more of: a peak inan X-ray powder diffraction (XRPD) diffractogram at a 20 value of18.3°2θ±0.1° as measured by x-ray powder diffraction using an x-raywavelength of 1.5406 Å; peaks in an XRPD diffractogram at 2θ values of17.2°2θ±0.1°, 18.3°2θ±0.1° and 19.5°2θ±0.1° as measured by x-ray powderdiffraction using an x-ray wavelength of 1.5406 Å; peaks in an XRPDdiffractogram at 2θ values of 18.5°2θ±0.1° and 20°2θ±0.1° as measured byx-ray powder diffraction using an x-ray wavelength of 1.5406 Å; an XRPDdiffractogram as substantially illustrated in Figure 24 (lots P1, R1,Q1), Figure 28 (lot R2), Figures 38 (lots A1, B1) or 39 (lots A1, B1);and/or Fourier transform infrared (FTIR) spectra as substantiallyillustrated in Figure 93 (lot C2).
 85. The 5-MeO-DMT benzoate of claim82, wherein the crystalline form is Pattern C.
 86. The 5-MeO-DMTbenzoate of claim 85, wherein the crystalline form Pattern C ischaracterised by one or more of: a minor broad endotherm with a peaktemperature of 108° C. in a differential scanning calorimetry (DSC)thermograph; a DSC thermograph as substantially illustrated in Figure 65or Figure 66; a peak in an X-ray powder diffraction (XRPD) diffractogramat a 2θ value of 10.3° 2θ±0.1° as measured by x-ray powder diffractionusing an x-ray wavelength of 1.5406 Å; an XRPD diffractogram assubstantially illustrated in Figure 68 (lot A1); and/or Fouriertransform infrared (FTIR) spectra as substantially illustrated in Figure93 (lot C1).
 87. The 5-MeO-DMT benzoate of claim 82, wherein thecrystalline form is Pattern D.
 88. The 5-MeO-DMT benzoate of claim 87,wherein the crystalline form Pattern D is characterised by one or moreof: an X-ray powder diffraction (XRPD) diffractogram as substantiallyillustrated in Figure 73 or Figure 74; an endothermic event in adifferential scanning calorimetry (DSC) thermograph at 118° C.; and/oran endothermic event in a DSC thermograph at 119° C.
 89. The 5-MeO-DMTbenzoate of claim 82, wherein the crystalline form is Pattern E.
 90. The5-MeO-DMT benzoate of claim 89, wherein the crystalline form Pattern Eis characterised by one or more of: an X-ray powder diffraction (XRPD)diffractogram as substantially illustrated in Figure 77 or Figure 78(lot D); a major bimodal endothermic event with peak temperatures of110.31° C. and 113.13° C. in a differential scanning calorimetry (DSC)thermograph; a minor endothermic event with a peak temperature of119.09° C. in a DSC thermograph; a DSC thermograph as substantiallyillustrated in Figure 79; and/or an XRPD diffractogram as substantiallyillustrated in Figure
 80. 91. A pharmaceutical composition comprisingthe 5-MeO-DMT benzoate of claim 81 and one or more pharmaceuticallyacceptable carriers or excipients formulated for administration one ormore times a day.
 92. A pharmaceutical composition comprising the5-MeO-DMT benzoate of claim 81 and one or more pharmaceuticallyacceptable carriers or excipients formulated for administration morethan one time a day.
 93. A pharmaceutical composition comprising the5-MeO-DMT benzoate of claim 81 and one or more pharmaceuticallyacceptable carriers or excipients formulated for administration twicedaily.
 94. The pharmaceutical composition of claim 93 formulated fornasal administration.
 95. An antidepressant pharmaceutical compositioncomprising the 5-MeO-DMT benzoate of claim 81 and one or morepharmaceutically acceptable carriers or excipients.
 96. Thepharmaceutical composition of claim 95 formulated for nasaladministration.
 97. An antianxiety pharmaceutical composition comprisingthe 5-MeO-DMT benzoate of claim 81 and one or more pharmaceuticallyacceptable carriers or excipients.
 98. The pharmaceutical composition ofclaim 97 formulated for nasal administration.
 99. An anti-addictionpharmaceutical composition comprising the 5-MeO-DMT benzoate of claim 81and one or more pharmaceutically acceptable carriers or excipients. 100.The pharmaceutical composition of claim 99 formulated for nasaladministration.